CN103601709A - Glucopyranosyl-substituted benzonitrile derivatives, pharmaceutical compositions containing such compounds, their use and process for their manufacture - Google Patents
Glucopyranosyl-substituted benzonitrile derivatives, pharmaceutical compositions containing such compounds, their use and process for their manufacture Download PDFInfo
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- 0 *c1ccc(Cc2cc([C@@]([C@@]([C@]3O)O)O[C@@](CO)[C@@]3O)ccc2C#N)cc1 Chemical compound *c1ccc(Cc2cc([C@@]([C@@]([C@]3O)O)O[C@@](CO)[C@@]3O)ccc2C#N)cc1 0.000 description 1
- QSOLGMQETJYQCG-RXFVIIJJSA-N CC(C)CCc1ccc(Cc2cc([C@@H]([C@@H]([C@H]3O)O)O[C@H](CO)[C@H]3O)ccc2C#N)cc1 Chemical compound CC(C)CCc1ccc(Cc2cc([C@@H]([C@@H]([C@H]3O)O)O[C@H](CO)[C@H]3O)ccc2C#N)cc1 QSOLGMQETJYQCG-RXFVIIJJSA-N 0.000 description 1
- DJJPACPHHWXNHC-GRIBUZNISA-N CCc1ccc(Cc2cc(C([C@@H]([C@H]3OC(C)=O)OC(C)=O)O[C@H](COC(C)=O)[C@H]3OC(C)=O)ccc2N)cc1 Chemical compound CCc1ccc(Cc2cc(C([C@@H]([C@H]3OC(C)=O)OC(C)=O)O[C@H](COC(C)=O)[C@H]3OC(C)=O)ccc2N)cc1 DJJPACPHHWXNHC-GRIBUZNISA-N 0.000 description 1
- AVRVYTWMJXPSFN-VKQJQLINSA-N CO[C@@]([C@@H]([C@H]1O)O)(c(cc2COCc3ccccc3)ccc2Br)OC(CO)[C@H]1O Chemical compound CO[C@@]([C@@H]([C@H]1O)O)(c(cc2COCc3ccccc3)ccc2Br)OC(CO)[C@H]1O AVRVYTWMJXPSFN-VKQJQLINSA-N 0.000 description 1
- NIEQZZXEZYUFMQ-UHFFFAOYSA-N COc(cc1)ccc1C(c1cc(Br)ccc1Cl)=O Chemical compound COc(cc1)ccc1C(c1cc(Br)ccc1Cl)=O NIEQZZXEZYUFMQ-UHFFFAOYSA-N 0.000 description 1
- LATBQJFNPVKUAK-UKYVYKIHSA-N CS(c1ccc(Cc2cc([C@@H]([C@@H]([C@H]3O)O)O[C@H](CO)[C@H]3O)ccc2C#N)cc1)=O Chemical compound CS(c1ccc(Cc2cc([C@@H]([C@@H]([C@H]3O)O)O[C@H](CO)[C@H]3O)ccc2C#N)cc1)=O LATBQJFNPVKUAK-UKYVYKIHSA-N 0.000 description 1
- OWPARZXOXYSXQB-UHFFFAOYSA-N Cc(cc1CO)ccc1Br Chemical compound Cc(cc1CO)ccc1Br OWPARZXOXYSXQB-UHFFFAOYSA-N 0.000 description 1
- RITSUWAEFHPALO-BDHVOXNPSA-N N#Cc1c(Cc2ccc(C3(CC3)O)cc2)cc([C@@H]([C@@H]([C@H]2O)O)O[C@H](CO)[C@H]2O)cc1 Chemical compound N#Cc1c(Cc2ccc(C3(CC3)O)cc2)cc([C@@H]([C@@H]([C@H]2O)O)O[C@H](CO)[C@H]2O)cc1 RITSUWAEFHPALO-BDHVOXNPSA-N 0.000 description 1
- LXGWVHTZIVDUEB-QUIYGKKVSA-N N#Cc1ccc(C([C@@H]([C@H]2O)O)O[C@H](CO)[C@H]2O)cc1Cc(cc1)ccc1Cl Chemical compound N#Cc1ccc(C([C@@H]([C@H]2O)O)O[C@H](CO)[C@H]2O)cc1Cc(cc1)ccc1Cl LXGWVHTZIVDUEB-QUIYGKKVSA-N 0.000 description 1
- HOSDGRTZNROBNY-ADAARDCZSA-N N#Cc1ccc(Cc2cc([C@@H]([C@@H]([C@H]3O)O)O[C@H](CO)[C@H]3O)ccc2C#N)cc1 Chemical compound N#Cc1ccc(Cc2cc([C@@H]([C@@H]([C@H]3O)O)O[C@H](CO)[C@H]3O)ccc2C#N)cc1 HOSDGRTZNROBNY-ADAARDCZSA-N 0.000 description 1
- OMPPIVJMSRJCTN-OBKDMQGPSA-N N#Cc1ccc([C@@H]([C@@H]([C@H]2O)O)O[C@H](CO)[C@H]2O)cc1Cc1ccc(C(F)(F)F)cc1 Chemical compound N#Cc1ccc([C@@H]([C@@H]([C@H]2O)O)O[C@H](CO)[C@H]2O)cc1Cc1ccc(C(F)(F)F)cc1 OMPPIVJMSRJCTN-OBKDMQGPSA-N 0.000 description 1
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- C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D309/10—Oxygen atoms
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- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/351—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom not condensed with another ring
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- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
- C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
The invention relates to a glucopyranosyl-substituted benzonitrile derivatives defined in formula (I), including the tautomers, the stereoisomers thereof, the mixtures thereof and the salts thereof. The compounds according to the invention are suitable for the treatment of metabolic disorders. In formula (I), R3 is defined as in the description.
Description
The application is to be May 2, application number in 2007 the dividing an application for the application for a patent for invention of " the cyanobenzene derivative being replaced by glucopyranose base, containing the pharmaceutical composition of described compound, its purposes and preparation method thereof " that be 200780015928.5 (international application no is PCT/EP2007/054248), denomination of invention the applying date.
The present invention relates to the cyanobenzene derivative being replaced by glucopyranose base of general formula I:
Radicals R wherein
3definition sees below, and comprises its tautomer, steric isomer, mixture and salt thereof.The invention still further relates to the pharmaceutical composition and the purposes of compound of the present invention in the pharmaceutical composition for the preparation for the treatment of metabolic disturbance that contain formula I compound of the present invention.In addition, the present invention relates to the method for the preparation of pharmaceutical composition of the present invention and compound.
In the literature, propose the inhibiting compound of sodium dependent glucose cotransporter SGLT2 tool to be used for the treatment of disease, especially diabetes.
From international application case WO2005/092877 and the known aromatic group being replaced by glucopyranose base of open case wherein quoted and preparation and active as the possibility of SGLT2 inhibitor thereof.
Goal of the invention
Target of the present invention is for finding the novel cyanobenzene derivative being replaced by glucopyranose base, and especially those are for the activated derivative of sodium dependent glucose cotransporter SGLT (especially SGLT2).Another target of the present invention is for finding and the similar Compound Phase ratio of known structure, in vitro and/or in vivo sodium dependent glucose cotransporter SGLT2 tool strengthened to restraining effect and/or has the benzene derivative being replaced by glucopyranose base of better pharmacology or pharmacokinetic properties.
Another target of the present invention is for providing the novel medicament compositions that is suitable for prevention and/or treatment metabolic disturbance, especially diabetes.
Directly from above, address following explanation, other targets of the present invention will become apparent to those skilled in the art.
Goal of the invention
In first aspect, the present invention relates to the cyanobenzene derivative being replaced by glucopyranose base of formula I, comprise its tautomer, steric isomer or its mixture; And physiologically acceptable salt
Wherein
R
3represent hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl group, sec.-propyl, butyl, sec-butyl, isobutyl-, the tertiary butyl, 3-methyl-Ding-1-base, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-hydroxyl-cyclopropyl, 1-hydroxyl-cyclobutyl, 1-hydroxyl-cyclopentyl, 1-hydroxyl-cyclohexyl, difluoromethyl, trifluoromethyl, pentafluoroethyl group, 2-hydroxyl-ethyl, hydroxymethyl, 3-hydroxyl-propyl, 2-hydroxy-2-methyl-propyl-1-base, 3-hydroxy-3-methyl-Ding-1-base, 1-hydroxyl-1-methyl-ethyl, 2, 2, the fluoro-1-hydroxyl-1-of 2-tri-methyl-ethyl, 2, 2, the fluoro-1-hydroxyl-1-of 2-tri-trifluoromethyl-ethyl, 2-methoxyl group-ethyl, 2-oxyethyl group-ethyl, hydroxyl, difluoro-methoxy, trifluoromethoxy, 2-methoxyl group-oxyethyl group, methylthio group, methylsulfinyl, methyl sulphonyl, ethyl sulfinyl, ethylsulfonyl, trimethyl silyl and cyano group,
Or derivatives thereof: wherein one or more hydroxyl of β-D-glucopyranose base is selected from (C
1-18alkyl) carbonyl, (C
1-18alkyl) oxygen base carbonyl, phenylcarbonyl group and phenyl-(C
1-3the group acidylate of alkyl)-carbonyl.
On compound of the present invention and physiology thereof, acceptable salt has valuable pharmacological characteristics, especially the restraining effect to sodium dependent glucose cotransporter SGLT (especially SGLT2).In addition compound of the present invention can have the restraining effect to sodium dependent glucose cotransporter SGLT1.Compare with the possible restraining effect to SGLT1, compound of the present invention preferably selectivity suppresses SGLT2.
The present invention also relates to acceptable salt on physiology that compound of the present invention and mineral acid or organic acid form.
The present invention also relates to pharmaceutical composition, it contains acceptable salt at least one compound of the present invention or physiology of the present invention, optionally together with one or more inert support and/or thinner.
The present invention also relates to acceptable salt at least one compound of the present invention or its physiology and be suitable for treatment or prevention can be by the purposes suppressing in the disease of sodium dependent glucose cotransporter SGLT (especially SGLT2) impact or the pharmaceutical composition of illness in preparation.
The present invention also relates to acceptable salt at least one compound of the present invention or its physiology and be suitable for treating the purposes in the pharmaceutical composition of one or more metabolic disturbance in preparation.
In another aspect, the present invention relates at least one compound of the present invention or a kind of its physiology acceptable salt is degenerating for the preparation of prevention pancreatic beta cell and/or for improving and/or recover the purposes of the pharmaceutical composition of Pancreatic beta cells function.
In another aspect, the present invention relates to acceptable salt at least one compound of the present invention or a kind of its physiology for the preparation of preventing, slow down, postpone or treating due to the purposes having in the pharmaceutical composition of disease that in this patient body needing, liver fat abnormal accumulation causes or illness.
The present invention also relates to the purposes of acceptable salt in the pharmaceutical composition for the preparation of inhibition sodium dependent glucose cotransporter SGLT (especially SGLT2) at least one compound of the present invention or its physiology.
The invention still further relates to the method for the preparation of pharmaceutical composition of the present invention, it is characterized in that by non-chemical method acceptable salt on compound of the present invention or a kind of its physiology together with in one or more inert support and/or thinner.
The present invention also relates to the method for the preparation of the compound of general formula I of the present invention, it is characterized in that
A) be preparation as the compound of defined general formula I and below above,
At Lewis acid (Lewis) or bronsted acid (Br
nsted acid) under existence, the compound of general formula I I is reacted with reductive agent, can make protecting group while or the cracking in succession of any existence simultaneously;
Wherein
R ' represents H, C
1-4alkyl, (C
1-18alkyl) carbonyl, (C
1-18alkyl) oxygen base carbonyl, aryl carbonyl and aryl-(C
1-3alkyl)-carbonyl, wherein alkyl or aryl can be by halogen list or polysubstituted;
R
8a, R
8b, R
8c, R
8drepresent independently of one another hydrogen or allyl group, benzyl, (C
1-4alkyl) carbonyl, (C
1-4alkyl) oxygen base carbonyl, aryl carbonyl, aryl-(C
1-3alkyl)-carbonyl and aryl-(C
1-3alkyl)-oxygen base carbonyl or R
ar
br
csi base or ketal or acetal radical, especially alkylidene group or aryl alkylene ketal or acetal radical, simultaneously two adjacent group R in each situation
8a, R
8b, R
8c, R
8dcan form cyclic ketal or acetal radical or 1,2-, bis-(C
1-3alkoxyl group)-1,2-bis-(C
1-3alkyl)-ethylene bridge, above-mentioned ethylene bridge is substituted two together with two Sauerstoffatoms and two relevant carbon atoms formation of pyranose ring simultaneously
alkane ring, especially 2,3-dimethyl-2,3-bis-(C
1-3alkoxyl group)-Isosorbide-5-Nitrae-bis-
alkane ring, and alkyl, allyl group, aryl and/or benzyl can be by halogen or C simultaneously
1-3alkoxyl group list or polysubstituted, and benzyl also can be through two-(C simultaneously
1-3alkyl) amino replacement; And
R
a, R
b, R
crepresent independently of one another C
1-4alkyl, aryl or aryl-C
1-3alkyl, wherein aryl or alkyl can be by halogen lists or polysubstituted;
Aryl described in the definition of above-mentioned group refers to phenyl or naphthyl simultaneously, is preferably phenyl;
And R wherein
3base is as above and below defined; Or
B) for preparing the compound of general formula I,
The compound of general formula III
R wherein
8a, R
8b, R
8c, R
8dand R
3as above and below defined, its restricted condition is at least one is selected from R
8a, R
8b, R
8c, R
8dsubstituting group be not hydrogen;
To not be the protecting group R of hydrogen
8a, R
8b, R
8c, R
8dcracking; And
If desired, by acidylate, make thus obtained compound of Formula I be converted into the acyl compounds of corresponding general formula I, and/or
If essential, by any protecting group cracking used in above-mentioned reaction, and/or
If desired, thus obtained compound of Formula I is split as to its steric isomer, and/or
If desired, thus obtained compound of Formula I is converted into its salt, especially for medicinal use, is converted into acceptable salt on its physiology.
Other aspects of the present invention relate to as in reaction scheme below and the novel intermediates described in experimental section.
Detailed Description Of The Invention
Aspect of the present invention, be in particular compound, medical composition and its use, relate to as the cyanobenzene derivative or derivatives thereof being replaced by glucopyranose base of defined general formula I above and below, comprise acceptable salt on its tautomer, steric isomer or its mixture and physiology thereof.
In following substituting preferred embodiment of the present invention, describe:
According to the first embodiment of the present invention, R
3represent hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl group, sec.-propyl, butyl, sec-butyl, isobutyl-, the tertiary butyl, 3-methyl-Ding-1-base, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, difluoromethyl, trifluoromethyl, pentafluoroethyl group, 2-hydroxyl-ethyl, methylol, 3-hydroxyl-propyl, 2-hydroxy-2-methyl-propyl-1-base, 3-hydroxy-3-methyl-Ding-1-base, 1-hydroxyl-1-methyl-ethyl, 2, 2, the fluoro-1-hydroxyl-1-of 2-tri-methyl-ethyl, 2, 2, the fluoro-1-hydroxyl-1-of 2-tri-trifluoromethyl-ethyl, 2-methoxyl group-ethyl, 2-oxyethyl group-ethyl, hydroxyl, difluoro-methoxy, trifluoromethoxy, 2-methoxyl group-oxyethyl group, methylthio group, methylsulfinyl, methyl sulphonyl, ethyl sulfinyl, ethylsulfonyl, TMS or cyano group.
According to the second embodiment of the present invention, R
3represent hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, difluoro-methoxy, trifluoromethoxy, 2-methoxyl group-oxyethyl group, methylthio group, methylsulfinyl, methyl sulphonyl, ethyl sulfinyl, ethylsulfonyl, TMS or cyano group.
According to the 3rd embodiment of the present invention, R
3represent methyl, ethyl, propyl group, sec.-propyl, butyl, sec-butyl, isobutyl-, the tertiary butyl, 3-methyl-Ding-1-base, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, difluoromethyl, trifluoromethyl, pentafluoroethyl group, 2-hydroxyl-ethyl, methylol, 3-hydroxyl-propyl, 2-hydroxy-2-methyl-propyl-1-base, 3-hydroxy-3-methyl-Ding-1-base, 1-hydroxyl-1-methyl-ethyl, 2,2, the fluoro-1-hydroxyl-1-of 2-tri-methyl-ethyl, 2, the fluoro-1-hydroxyl-1-of 2,2-tri-trifluoromethyl-ethyl, 2-methoxyl group-ethyl or 2-oxyethyl group-ethyl.
According to the 4th embodiment of the present invention, R
3represent methyl, ethyl, propyl group, sec.-propyl, butyl, sec-butyl, isobutyl-, the tertiary butyl, 3-methyl-Ding-1-base, difluoromethyl, trifluoromethyl or pentafluoroethyl group.
According to the 5th embodiment of the present invention, R
3representative ring propyl group, cyclobutyl, cyclopentyl or cyclohexyl.
According to the 6th embodiment of the present invention, R
3represent 1-hydroxyl-cyclopropyl, 1-hydroxyl-cyclobutyl, 1-hydroxyl-cyclopentyl or 1-hydroxyl-cyclohexyl.
According to the 7th embodiment of the present invention, R
3represent 2-hydroxyl-ethyl, hydroxymethyl, 3-hydroxyl-propyl, 2-hydroxy-2-methyl-propyl-1-base, 3-hydroxy-3-methyl-Ding-1-base, 1-hydroxyl-1-methyl-ethyl, 2,2, the fluoro-1-hydroxyl-1-of 2-tri-methyl-ethyl, 2, the fluoro-1-hydroxyl-1-of 2,2-tri-trifluoromethyl-ethyl, 2-methoxyl group-ethyl or 2-oxyethyl group-ethyl.
According to the 8th embodiment of the present invention, R
3represent 2-hydroxyl-ethyl, hydroxymethyl, 3-hydroxyl-propyl or 1-hydroxyl-1-methyl-ethyl.
According to the 9th embodiment of the present invention, R
3represent hydroxyl, difluoro-methoxy, trifluoromethoxy or cyano group.
According to the tenth embodiment of the present invention, R
3represent methyl, ethyl, propyl group, sec.-propyl, difluoromethyl, trifluoromethyl or pentafluoroethyl group.
Preferably, as defined all hydroxyls of β-D-glucopyranose base be not substituted or only the hydroxyl O-6 of β-D-glucopyranose base be substituted.Preferred substituting group is selected from (C
1-8alkyl) carbonyl, (C
1-8alkyl) oxygen base carbonyl and phenylcarbonyl group.More preferably substituting group is selected from ethanoyl, methoxycarbonyl and ethoxy carbonyl, especially ethanoyl and ethoxy carbonyl.
Unless otherwise indicated, otherwise and hereinafter, in the nomenclature of structural formula used, as showing, the substituent key of cyclic group (base is benzyl ring for example) towards the center of cyclic group, represents the bonding any free position to thering is the cyclic group of H atom of this substituting group above.
Can the known synthetic method of use principle obtain compound of the present invention.Preferably by the method following of the present invention below more describing in detail, obtain these compounds.
Can from D-Glucose acid lactone or derivatives thereof, synthesize the glucose-derivative (scheme 1) of formula II of the present invention by adding the benzyl benzene compound of the organometallic compound form of wanting.
Scheme 1: organometallic compound is added to Gluconolactone
Preferably from the benzyl halide benzene compound of general formula I V, start to carry out the reaction of scheme 1, wherein Hal represents chlorine, bromine or iodine.R in scheme 1
1represent cyano group or can be converted into subsequently the group of cyano group; for example for example acetal or thiazole of the aldehyde functional group of chlorine, bromine, carboxyl, carboxylicesters, carboxylic acid amides or derivatives thereof, boron or silyl, protected or crested, or the amido functional group of protected or crested be nitro for example.Can be by so-called halogen-metal exchange reaction or by metal being inserted to Grignard reagent (Grignard) or the lithium reagent (V) of preparing benzyl benzene in carbon-halogen bond from corresponding chlorination, bromination or iodate benzyl benzene IV.Can (for example) with for example just, the organolithium compound of the second month in a season or tert-butyl lithium carries out halogen-metal exchange to synthesize corresponding lithium compound V.Also can without or have under other salt of for example lithium chloride that can accelerate metallization processes exist, the halogen-metal exchange by the suitable Grignard reagent with for example bromination isopropyl-magnesium or bromination sec-butyl magnesium or isopropyl-magnesium chloride or chlorination sec-butyl magnesium or di-isopropyl magnesium or di-sec-butyl magnesium produces similar magnesium compound; Also can produce the specific metallization organo-magnesium compound (for example, referring to Angew.Chem.2004,116,3396-3399 and Angew.Chem.2006,118,165-169 and the document wherein quoted) that turns from appropriate precursors original position.In addition, also can adopt owing to for example butyl magnesium chloride or butyl magnesium bromide or isopropyl-magnesium chloride or bromination isopropyl-magnesium are mixed to the salt complex of produced organo-magnesium compound with butyllithium and (for example see Angew.Chem.2000,112,2594-2596 and Tetrahedron Lett.2001,42,4841-4844 and the document wherein quoted).Halogen-metal exchange reaction is preferably at 40 ℃ to-100 ℃, especially preferably at 10 ℃ to-80 ℃ for example, at inert solvent or its mixture (ether, two
alkane, tetrahydrofuran (THF), toluene, hexane, methyl-sulphoxide, methylene dichloride or its mixture) in carry out.Optionally with for example metal-salt of cerous compounds, zinc chloride or zinc bromide, indium chloride or indium bromide, make thus obtained magnesium or the derivative compound of lithium turn metallization to form other organometallic compound (V) that is suitable for addition.Or also can prepare organometallic compound V by metal being inserted in the carbon-halogen bond of halogenated aromatic compound IV.Lithium or magnesium are the metal element that is suitable for this conversion.Insertion can be at-80 to 100 ℃, preferably at the temperature within the scope of-70 to 40 ℃ at for example ether, two
in the solvent of alkane, tetrahydrofuran (THF), toluene, hexane, methyl-sulphoxide and composition thereof, realize.In the situation that there is not spontaneous reaction, may need metal to activate for example with glycol dibromide, iodine, trimethylsilyl chloride, acetic acid, hydrochloric acid and/or supersound process in advance.Make reaction that organometallic compound V is added to Gluconolactone or derivatives thereof (VI) preferably between 40 ℃ to-100 ℃, especially preferably at the temperature of 0 to-80 ℃, in inert solvent or its mixture, carry out, to obtain formula II compound.Although all above-mentioned reactions preferably complete in the inert atmosphere of for example argon gas and nitrogen, it also can carry out in air.Metallization and/or linked reaction also can be carried out in the microreactor that can carry out with high rate of exchange and/or micro-mixer; For example similar with the method described in WO2004/076470.For metallized phenyl V being added to the appropriate solvent of the Gluconolactone VI suitably being protected, be (for example) ether, glycol dimethyl ether, benzene, toluene, methylene dichloride, hexane, tetrahydrofuran (THF), two
alkane, N-Methyl pyrrolidone and composition thereof.Addition reaction can be under without any other adjuvant or at for example BF
3* OEt
2or Me
3under existing, the promotor of SiCl carries out (seeing M.Schlosser in the situation of the coupling collocation thing of deferred reaction, Organometallics in Synthesis, John Wiley & Sons, Chichester/New York/Brisbane/Toronto/Singapore, 1994).Substituent R in scheme 1
8preferably be defined as benzyl, substituted benzyl, allyl group, trialkylsilkl, be especially preferably trimethyl silyl, triisopropyl silyl, allyl group, 4-methoxy-benzyl and benzyl.If two adjacent substituent R
8link together, these two substituting groups be preferably benzylidene acetal, 4-methoxyl group benzylidene acetal, sec.-propyl ketal part or with by 2 of butane, be connected with the adjacent oxygen atom of pyranose with 32,3-dimethoxy-butylidene forms two
alkane.R ' base preferably represents hydrogen, C
1-4alkyl, C
1-4alkyl-carbonyl or C
1-4alkyl oxy carbonyl, is especially preferably hydrogen, methyl or ethyl.After being added to Gluconolactone VI, organometallic compound V or derivatives thereof introduces R ' base.If R ' equals hydrogen or C
1-4alkyl, under the acid of for example acetic acid, methylsulfonic acid, toluenesulphonic acids, sulfuric acid, trifluoroacetic acid or hydrochloric acid exists with alcohols or the treatment reaction solution of for example methyl alcohol or ethanol.Also after can making different head (anomeric) hydroxyl and the suitable electrophilic reagent of for example methyl-iodide, methyl-sulfate, iodoethane, ethyl sulfate, Acetyl Chloride 98Min. or diacetyl oxide react to prepare hydrogen compound II, be connected R ' under alkali by for example triethylamine, ethyl diisopropyl amine, sodium carbonate or salt of wormwood or cesium carbonate, sodium hydroxide or potassium hydroxide or cesium hydroxide exists.Also can before adding electrophilic reagent, for example, with () sodium hydride, make hydroxyl deprotonation.During connecting R ', if protecting group R
8at the corresponding protonated compound of adopt generation, (be R
8equal the Compound I I of H) unstable under reaction conditions, R
8cleavable.
The synthetic of halogenated aromatic compound that can use the standard conversion in organic chemistry or method that at least technical literature from organic synthesis is known to carry out formula IV (sees J.March, Advanced Organic Reactions, Reactions, Mechanisms, and Structure, the 4th edition, John Wiley & Sons, Chichester/New York/Brisbane/Toronto/Singapore, 1992 and the document wherein quoted etc.).More particularly; in different monographs, describe in detail transition metal and organometallic compound (are for example shown in to L.Brandsma for the synthesis of aromatic substance; S.F.Vasilevsky; H.D.Verkruijsse; Application of Transition Metal Catalysts in Organic Synthesis; Springer-Verlag, Berlin/Heidelberg, 1998; M.Schlosser, Organometallics in Synthesis, John Wiley & Sons, Chichester/New York/Brisbane/Toronto/Singapore, 1994, P.J.Stang, F.Diederich, Metal-Catalyzed Cross-Coupling Reactions, Wiley-VCH, Weinheim, 1997 and the document wherein quoted).Hereinafter described synthetic schemes is witnessed by example.In addition, also can use identical synthetic method make aglycon part and exist pyranose part to be combined.
Scheme 2: diaryl ketone fragment synthetic
Scheme 2 has shown that application friedel-crafts (Friedel-Crafts) acylation condition or its variant start from Benzoyl chloride and second aromatic group the precursor compound that preparation can be used for the halogenated aromatic compound of synthesis type IV.R in scheme 2
1represent cyano group or can be converted into subsequently the group of cyano group, for example for example thioacetal or thiazole of the aldehyde functional group of chlorine, bromine, carboxyl, carboxylicesters, carboxylic acid amides or derivatives thereof, protected or crested, or the amido functional group of protected or crested be nitro for example.This classical reaction has wide substrate scope, and conventionally at for example AlCl using with catalysis or stoichiometric amount
3, FeCl
3, iodine, iron, ZnCl
2, sulfuric acid or trifluoromethanesulfonic acid catalyzer carry out under existing.Also can use corresponding carboxylic acid, acid anhydrides, ester or cyanobenzene to replace Benzoyl chloride.Reaction, preferably at-30 to 120 ℃, is preferably carried out at the temperature of 30 to 100 ℃ in the chlorinated hydrocarbon of for example methylene dichloride and 1,2-ethylene dichloride.Yet, also can solvent-free reaction or the reaction in microwave oven.
Scheme 3: diaryl ketone and diarylcarbinols are reduced to diarylmethanes
In scheme 3, substituent R represents C
1-3alkyl or aryl, and R
1represent cyano group or can be converted into subsequently the group of cyano group; for example for example acetal or thiazole of the aldehyde functional group of chlorine, bromine, carboxyl, carboxylicesters, carboxylic acid amides or derivatives thereof, boron or silyl, protected or crested, or the amido functional group of protected or crested be nitro for example.Can start to obtain diarylmethanes with one or two reactions steps from diaryl ketone or diarylcarbinols.Diaryl ketone can two steps be reduced to diarylmethanes by corresponding diphenyl-carbinol or with a step.In two step variants, for example, with for example metal hydride (NaBH
4, LiAlH
4or iBu
2alH) reductive agent reductone is to form alcohol.At for example BF
3* OEt
2, InCl
3or AlCl
3lewis acid or for example the bronsted acid of hydrochloric acid, sulfuric acid, trifluoroacetic acid or acetic acid exist under with for example Et
3siH, NaBH
4or Ph
2the reductive agent of SiClH makes gained alcohol be converted into wanted ditan.Can (for example) with for example Et
3the silicomethane of SiH, for example NaBH
4hydroborate or LiAlH for example
4aluminum hydride at for example BF
3* OEt
2, three (pentafluorophenyl group) borine, trifluoroacetic acid, hydrochloric acid, aluminum chloride or InCl
3lewis acid or the bronsted acid one step process that carries out starting to obtain from ketone ditan under existing.Reaction, preferably at-30 to 150 ℃, preferably for example, is carried out at the temperature of 20 to 100 ℃ in the solvent of for example halon (methylene dichloride, toluene, acetonitrile or its mixture).Hydrogen reducing under the transition-metal catalyst of for example Pd/C exists is another possibility synthetic method.Also can be according to the reduction reaction of Wo Fu-Qi Xinuo (Wolff-Kishner) or its variant.First with hydrazine or derivatives thereof for example 1, two (t-butyldimethylsilyl) hydrazines of 2-make ketone be converted into hydrazone, and hydrazone decomposes to form ditan and nitrogen under highly basic reaction conditions and heating.Reaction can a reactions steps be carried out or carry out afterwards with two separated hydrazone or derivatives thereofs of independent reactions steps.Appropriate base comprises (for example) KOH, NaOH or KOtBu in the solvent of for example ethylene glycol, toluene, DMSO, 2-(2-butoxy oxyethyl group) ethanol or the trimethyl carbinol; Also can be solvent-free reaction.Reaction can, between 20 to 250 ℃, preferably be carried out at the temperature between 80 to 200 ℃.The condition of replacement of the alkaline condition of Wo Fu-Qi Xinuo reduction is Clemmensen (Clemmensen) reduction, and it occurs under acidic conditions, also can use herein.In diarylcarbinols, first alcohol functional group also can make the transition as better leaving group, for example chlorine, bromine, iodine, acetoxyl, carbonyldioxy, phosphate or sulfate; The reduction step subsequently that forms diarylmethanes is extensively described in organic chemistry document.
Scheme 4: diarylmethanes unit and may precursor compound synthetic
R in scheme 4
1represent cyano group or can be converted into subsequently the group of cyano group; for example for example acetal or thiazole of the aldehyde functional group of chlorine, bromine, carboxyl, carboxylicesters, carboxylic acid amides or derivatives thereof, boron or silyl, protected or crested, or the amido functional group of protected or crested be nitro for example.Term " Alk " represents C
1-4alkyl and each substituent R are independently from each other H, C
1-3alkyl and C
1-3alkoxyl group.Scheme 4 is described self-metallization phenyl and is started synthesis of diaryl methane and possibility precursor compound thereof.Can be by for example, halogen-metal exchange reaction with () butyllithium, isopropyl-magnesium halogenide or di-isopropyl magnesium or by metal element being inserted to the aromatic substance of synthesizing lithium or magnesium replacement in halogen-carbon bond from chlorination, bromination or iodinated aromatic compounds.Can react by the boron electrophilic reagent with for example boric acid ester or derivatives thereof from these metallization phenyl and obtain for example corresponding compound replacing through boron of boric acid, boric acid ester or di alkylaryl borine.In addition, also can or intend halogenated precursors and two boron or borane compound and prepare boryl (borylated) aromatic substance (for example seeing Tetrahedron Lett.2003,4895-4898 page and the document wherein quoted) through the transition metal-catalyzed reaction of for example palladium from corresponding halogenation.The phenyl compound of lithium or magnesium replacement is for example added to, in phenyl aldehyde (step 3) and phenylformic acid or derivatives thereof (step 4) (benzamide, cyanobenzene or the Benzoyl chloride of benzoic ether, for example Wen Ruibai (Weinreb) type).These reactions in principle can be under without other transition-metal catalysts or are not turned in another metal situation that metal turns to for example cerium, indium or zinc and carry out; Sometimes it is favourable using one of aftermentioned alternative method.Can aryl boric acid for example be added in phenyl aldehyde, so that each diarylcarbinols (seeing Adv.Synth.Catal.2001,343-350 page and the document wherein quoted) to be provided by rhodium catalyst.In addition, can be regulated by transition metal, its complex compound or the salt of for example palladium and make aryl boric acid, its ester, di alkylaryl borine or aryl trifluoro boric acid ester and Benzoyl chloride coupling to produce diaryl ketone.The phenyl that can make to metallize reacts to obtain diarylmethanes with the benzyl electrophilic reagent of for example benzyl chloride, bromotoluene or benzyl iodide.The phenyl compound of lithium or magnesium derivative advantageously but not total necessarily reaction (for example seeing Org.Lett.2001,3,2871-2874 and the document wherein quoted) under the transition metal of for example copper, iron or palladium exists.From lithium or magnesium, turn metal and turn to (for example) boron, tin, silicon or zinc (for example) corresponding aromatics boric acid, stannane, silicomethane or zn cpds are provided respectively, it can carry out for example, linked reaction with the benzyl electrophilic reagent of () benzyl halide compound, benzyl carbonic ether, benzyl phosphoric acid ester, benzyl sulphonate or benzyl carboxylate.Reaction is carried out (for example seeing Tetrahedron Lett.2004,8225-8228 page and Org.Lett.2005,4875-4878 page and the document wherein quoted) under the transition metal of for example palladium, nickel, rhodium, copper or iron exists.
Scheme 5: the introducing of cyano group part
Scheme 5 has shown that the different steps at synthetic target molecule makes cyano group residue be connected in the possible path of center phenyl.The linked reaction of the suitable cyano group source of for example sodium cyanide, Repone K, zinc cyanide or the cupric cyanide that can mediate by transition metal and halogenation or plan halogenated phenyl is introduced cyano group.Suitable catalyst can be derived from for example transition metal of palladium, rhodium, nickel, iron or copper, these transition metal for example palladium/carbon basic form, with the salt of for example Palladous chloride, palladium bromide or acid chloride or with for example triphenylphosphine, tri-butyl phosphine or 1, the alkene of the complex compound of the phosphine of 1 '-bis-(diphenylphosphino) ferrocene (dppf) or for example dibenzalacetone is used.Active catalyst can original position produce or produce before being added into reaction mixture.The additive that is for example the zinc of element or salt can be favourable (seeing Tetrahedron Lett.2005,46,1849-1853 and Tetrahedron Lett.2005,46,1815-1818 and the document wherein quoted).Make or to be another feasible method (for example seeing Synth.Commun.1996,3709-3714 and the document wherein quoted) that adds cyano functional group by the corresponding zinc, magnesium or the lithium compound that obtain from chlorination, bromination or iodinated compounds in each metal insertion halogen bond are reacted with for example cyano group electrophilic reagent of p-methylphenyl alkylsulfonyl prussiate, cyanogen bromide or cyanic acid 2-pyridine by halogen metal permutoid reaction.
Scheme 6: introduce cyano group residue from aldehyde or carboxylic acid derivative
Another kind of cyano group be introduced as synthetic (scheme 6) starting from aldehyde or carboxylic acid amides.Aldehyde functional group self can itself, protected or crested introduces.The general protecting group of aldehyde functional group is acetals, but also can use other protecting groups (to see T.W.Greene, P.G.M.Wuts; Protective Groups in Organic Synthesis, John Wiley & Sons, Inc.; New York, 1999).The suitable screening agent of aldehyde functional group is (for example) alkene and thiazole.Can use (for example) azanol for example, mixing with () formic acid, concentrated hydrochloric acid, Tripyrophosphoric acid or pyridine-toluene to make aldehyde be converted into cyano functional group.Can formed intermediate oxime under these reaction conditionss is separated, dewater afterwards to produce final product.Also can use for example two trifluoroacetyl group azanols and NH
2oSO
3other azanol reagent and in without other reagent situations, obtain nitrile.Other available reagents are (for example) NH in acetic acid
4pO
4h
2and nitropropane, trimethyl silyl triazo-compound or S, S-dimethyl sulphide imide.
Carboxylic acid amides also can be suitable nitrile precursor.For example trifluoroacetic anhydride, Vanadium Pentoxide in FLAKES, POCl
3, CCl
4the combination of-phosphine, Cl
3the combination of COCl-amine, burgess (Burgess) reagent, Wei Simeier (Vilsmeyer) reagent, SOCl
2or the dewatering agent of cyanuryl chloride transforms.Also can, from corresponding monoalkylation carboxylic acid amides, carboxylic acid, ester or carboxyl acyl chloride compound, at next pot of not separated any intermediate situation, form nitrile.
Scheme 7: introduce cyano group residue from aniline precursor
The method of the introducing nitrile functionality of having set up is reacted for the so-called mountain De Maier (Sandmeyer) of the corresponding diazonium compound with cupric cyanide and diazotization acquisition that can be by each anils.Diazonium compound synthetic and subsequently cyano group duplicate removal nitrogenization prove widely in organic chemistry document.
Scheme 8: the another kind of diarylmethanes unit is synthetic
In scheme 8, shown for building the another kind of method of diarylmethanes unit.
The cyanobenzene that uses the commercially available adjacent fluorine that maybe can obtain by aforesaid method to replace.Under alkaline condition, make cyanobenzene that adjacent fluorine replaces with by R
3the phenylacetic acid alkyl esters reaction replacing (is for example shown in J.Org.Chem.55,1990,4817-4821; J.Heterocycl.Chem, 32,1995,1461-1466) ester cracking subsequently and decarboxylation (are for example shown in J.Heterocycl.Chem, 32,1995,1461-1466; Org.Prep.Proced.Int.37,2005,550-555) or directly take off alkoxy carbonyl and (for example see J.Med.Chem.46,2003,5249-5257; Angew.Chem.Int.Ed.47,2004,6493-6496).
For preparing the compound of general formula I, method of the present invention a) in, under Lewis acid or bronsted acid exist, the compound of general formula I I is reacted with reductive agent,
Wherein R ' and R
3as hereinbefore defined and
R
8a, R
8b, R
8c, R
8drepresent as hereinbefore defined and independently of one another (for example) ethanoyl, valeryl, benzoyl, tert-butoxycarbonyl, benzyl oxygen base carbonyl, allyl group, trialkylsilkl, benzyl or substituted benzyl or two adjacent group R in each situation
8a, R
8b, R
8c, R
8dform benzylidene acetal or isopropylidene ketal or by butylidene 2 and 3 be connected to pyranose ring Sauerstoffatom 2,3-dimethoxy-butylidene and form substituted two with above-mentioned group
alkane,
It can obtain as described above.
The suitable reductive agent of reaction comprises (for example) for example silicomethane, sodium borohydride, sodium cyanoborohydride, zinc borohydride, borine, lithium aluminum hydride, diisobutylaluminium hydride or means of samarium iodide of triethyl-silicane, tripropyl silicomethane, triisopropyl silicomethane or diphenylmethyl silane.Reduction without or have the suitable bronsted acid of for example hydrochloric acid, toluenesulphonic acids, trifluoroacetic acid or acetic acid or for example the Lewis acid of boron-trifluoride etherate, trifluoromethanesulfonic acid trimethyl silyl ester, titanium tetrachloride, tin tetrachloride, trifluoromethanesulfonic acid scandium or zinc iodide under existing, carry out.Depending on reductive agent and acid, reaction can be at for example methylene dichloride, chloroform, acetonitrile, toluene, hexane, ether, tetrahydrofuran (THF), two at the temperature between-60 ℃ to 120 ℃
in the solvent of alkane, ethanol, water or its mixture, carry out.Especially a suitable mixing of reagent for example, is comprised of () triethyl-silicane and boron-trifluoride etherate, these two kinds of compounds easily-60 ℃ with 60 ℃ of temperature under in acetonitrile or methylene dichloride, use.In addition can in for example Pd/C or Ruan, under existing, in the solvent of for example tetrahydrofuran (THF), ethyl acetate, methyl alcohol, ethanol, water or acetic acid, use hydrogen to be used for transforming by the transition-metal catalyst of (Raney) nickel.
Or, for preparation method b of the present invention) the compound of general formula I, in the compound of general formula III, protecting group cracking,
R wherein
3as hereinbefore defined and
R
8ato R
8drepresent one of defined protecting group above, for example acyl group, arylmethyl, allyl group, acetal, ketal or silyl, and its can (for example) compound by the formula II from as described above also originally obtain.
Should be appreciated that in above-mentioned synthetic method and can change radicals R
8ato R
8done or some groups.
Any acyl group protecting group used (for example) in aqueous solvent (for example, at water, isopropanol/water, acetic acid/water, tetrahydrofuran (THF)/water or two
in alkane/water) under the acid of for example trifluoroacetic acid, hydrochloric acid or sulfuric acid exists or under the alkali metal base of for example lithium hydroxide, sodium hydroxide or potassium hydroxide exists hydrolytic rupture or (for example) under iodate trimethyl silyl exists at the temperature between between 0 to 120 ℃, preferably non-proton property cracking at the temperature between between 10 to 100 ℃.Preferably by optionally under the solvent of for example acetic acid exists at the temperature between between 50 to 120 ℃ with the acid treatment of for example hydrochloric acid, or by optionally processing and make trifluoroacetyl group cracking with sodium hydroxide solution at the temperature between between 0 to 50 ℃ under the solvent of for example tetrahydrofuran (THF) or methyl alcohol exists.
Any acetal used or ketal protected (for example) in aqueous solvent (for example, at water, isopropanol/water, acetic acid/water, tetrahydrofuran (THF)/water or two
in alkane/water) under the acid of for example trifluoroacetic acid, hydrochloric acid or sulfuric acid exists hydrolytic rupture or (for example) under iodate trimethyl silyl exists at the temperature between between 0 to 120 ℃, preferably non-proton property cracking at the temperature between between 10 to 100 ℃.
Trimethyl silyl (for example) is in water, aequeous solvent mixture or for example cracking under the alkali of for example lithium hydroxide, sodium hydroxide, salt of wormwood or sodium methylate exists in the lower alcohol of methyl alcohol or ethanol.
In water-based or alcoholic solvent, for example the acid of hydrochloric acid, trifluoroacetic acid or acetic acid is also applicable to.For cracking in the organic solvent at for example ether, tetrahydrofuran (THF) or methylene dichloride, use for example fluoride reagents of tetrabutylammonium to be also applicable to.
(for example) under the catalyzer of for example palladium/charcoal exists in the suitable solvent of for example methyl alcohol, ethanol, ethyl acetate or Glacial acetic acid, optionally under the acid of adding hydrochloric acid for example at the temperature between between 0 to 100 ℃, but preferably under the surrounding temperature between between 20 to 60 ℃ and at 1 to 7 bar, but preferably under the hydrogen pressure of 3 to 5 bar, with hydrogen, make advantageously hydrocracking of benzyl, methoxy-benzyl or benzyloxycarbonyl.Yet 2,4-dimethoxy-benzyl is cracking in trifluoroacetic acid under methyl-phenoxide exists preferably.
Preferably by the acid treatment with for example trifluoroacetic acid or hydrochloric acid or by optionally using for example methylene dichloride, two
the solvent of alkane, methyl alcohol or ether is processed and is made the tertiary butyl or tert-butoxycarbonyl cracking with Iodotrimethylsilane.
In above-mentioned reaction, during reaction any reactive group of existing for example ethynyl, hydroxyl, amino, alkylamino or imino-can by after reaction again the GPF (General Protection False base of cracking protect.
For example, the protecting group of ethynyl can be trimethyl silyl or triisopropyl.2-hydroxyl isopropyl-2-base also can be used as protecting group.
For example, the protecting group of hydroxyl can be trimethyl silyl, ethanoyl, trityl, benzyl or THP trtrahydropyranyl.
The protecting group of amino, alkylamino or imino-can be (for example) formyl radical, ethanoyl, trifluoroacetyl group, ethoxy carbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxy-benzyl or 2,4-dimethoxy-benzyl.
In addition, as described above, removable its enantiomer and/or the diastereomer of being divided into of the compound of the general formula I obtaining.Therefore, for example, cis/trans mixture is removable is divided into its genial trans isomer, and to have the compound of at least one optical activity carbon atom separable be its enantiomer.
Therefore, for example, can make cis/trans mixture be split as its genial trans isomer by chromatography, can by known method itself, (compare Allinger N.L. and Eliel E.L. " Topics in Stereochemistry ", the 6th volume, Wiley Interscience, in 1971) make obtained compound separation of take the general formula I that racemoid exists can for example, based on the known method () of its physical-chemical difference use itself, by chromatogram and/or fractional crystallization, be split as its diastereomer as its optical antipode and the compound with the general formula I of at least 2 unsymmetrical carbons, if and obtain as these compounds of racemic form, can be resolved to enantiomer as above subsequently.
Preferably by the separated enantiomer of chirality phase upper prop or by recrystallization from optical activity solvent by with can with racemic compound form salt or for example the optically active substance (especially its acid and reactive derivative or alcohols) of the derivative of ester or acid amides react, and (for example) based on its dissolubility difference, make the non-enantiomer mixture separation of thus obtained salt or derivative make stage enantiomer separation, can make by the effect of suitable agent free enantiomorph discharge from pure diastereo-isomerism salt or derivative simultaneously.Conventional optical activity acid is (for example) D-type and L-type tartrate or dibenzoyl tartaric acid, di-o-tolyl tartrate, oxysuccinic acid, amygdalic acid, camphorsulfonic acid, L-glutamic acid, aspartic acid or quinic acid.Optical activity alcohol can be (for example) (+) or (-)-menthol and for example, and in acid amides, optical activity acyl group can be (+)-or (-)-menthyl oxygen base carbonyl.
In addition, the compound of formula I can be converted into its salt, is especially converted into acceptable salt on the physiology of the medicinal use forming with mineral acid or organic acid.The acid that can be used for this object comprises (for example) hydrochloric acid, Hydrogen bromide, sulfuric acid, methylsulfonic acid, phosphoric acid, fumaric acid, succsinic acid, lactic acid, citric acid, tartrate or toxilic acid.
In addition, the compound obtaining can be converted into mixture, for example, with amino acid, and the 1:1 or the 1:2 mixture that especially form with the a-amino acid of for example proline(Pro) or phenylalanine, these amino acid can have especially favourable characteristic, for example high-crystallinity.
Also can use the method described in following example advantageously to obtain compound of the present invention, these methods also can for example, combine from known in the literature method (method described in WO98/31697, WO01/27128, WO02/083066, WO03/099836, WO2004/063209, WO2005/092877 and WO2006/120208) with those skilled in the art for this purpose.
The present invention also relates to the novel intermediate compound described in reaction scheme above and described in experimental section below.
Particularly, following intermediate compound is other aspects of the present invention:
Wherein
R
8ato R
8drepresent as hereinbefore defined and preferably H or ethanoyl;
R ' represents H, methyl or ethyl as hereinbefore defined and preferably;
Alk represents C
1-4alkyl, preferably represents methyl or ethyl;
R
1represent as hereinbefore defined and preferably Br or CN, most preferably represent CN;
R
3as hereinbefore defined, for example cyclopropyl or cyclobutyl, and free following each group of choosing preferably: chlorine, bromine, methyl, ethyl, n-propyl, sec.-propyl, cyclopropyl, cyclobutyl, cyclopentyl, hydroxyl, cyano group;
LG represents leaving group, for example Br, I ,-O-(SO
2)-CF
3, be preferably-O-(SO
2)-CF
3;
U represents Cl, Br, I ,-O-CO-C
1-4alkyl ,-O-C (=O)-O-C
1-4alkyl or-OPO (O-C
1-4alkyl)
2; Be preferably Br.
As already mentioned, on the compound of general formula I of the present invention and physiology thereof, acceptable salt has valuable pharmacological characteristics, especially the restraining effect to sodium dependent glucose cotransporter SGLT (being preferably SGLT2).
The biological characteristics of compounds can be studied as follows:
Can in test set, prove that these materials suppress the ability of SGLT-2 activity, in this test set, there is CHO-K1 cell strain (ATCC CCL-61) or HEK293 cell strain (ATCC CRL-1573), described cell strain is by stable transfection expression vector pZeoSV (Invitrogen, EMBL deposits numbering L36849), the cDNA of the sequence that described cell strain contains coding mankind's sodium glucose cotransporters 2 (the Genbank number of asking for NM_003041) (CHO-hSGLT2 or HEK-hSGLT2).These cell strains will in sodium dependence mode
14alpha-Methyl-the glucopyranoside of C-mark (
14c-AMG, Amersham) be transported to cell interior.
SGLT-2 experiment is carried out as follows:
CHO-hSGLT2 cell is cultivated in Ham ' the s F12 substratum (BioWhittaker) that contains 10% foetal calf serum and 250 μ g/mL Zeocin (Invitrogen), and by HEK293-hSGLT2 cell cultures in the DMEM substratum that contains 10% foetal calf serum and 250 μ g/mL Zeocin (Invitrogen).By washing 2 times with PBS and processing cell separated from culture flask with trypsinase/EDTA subsequently.Add after cell culture medium, by cell centrifugation, be suspended from substratum and in Casy cell counter and count again.40,000, every hole cell is inoculated in white 96 orifice plates of poly--D-Lys coating and at 37 ℃, 5%CO
2lower overnight incubation.Cell is tested to damping fluid (Hanks balanced salt solution (Hanks Balanced Salt Solution), the CaCl of the NaCl of 137mM, the KCl of 5.4mM, 2.8mM with 250 μ l
2, 1.2mM MgSO
4and the HEPES of 10mM (pH7.4), 50 μ g/mL gentamicins (Gentamycin)) wash 2 times.Then 250 μ l experiment damping fluids and 5 μ l test compounds are added into each hole and culture plate is hatched 15 minutes in incubator again.Using 5 μ l10%DMSO as negative control.By by 5 μ l
14c-AMG (0.05 μ Ci) is added into each hole starts reaction.At 37 ℃, 5%CO
2lower cultivation is after 2 hours, cell is washed again with 250 μ l PBS (20 ℃) and then the NaOH of the 0.1N by interpolation 25 μ l (at 37 ℃ 5 minutes) make cytolysis.The MicroScint20 of 200 μ l (Packard) is added into each hole and hatches again 20 minutes 37 ℃ of continuation.After this cultivates, in Topcount (Packard), use
14the measurement of C flicker formula absorbs
14the intensity of radioactivity of C-AMG.
For measuring the selectivity for mankind SGLT1, set up similar test, in this test, the cDNA (Genbank Acc. NM_000343) of hSGLT1 replaces hSGLT2cDNA at CHO-K1 or HEK293 cells.
The EC of compound of the present invention
50value is lower than 1000nM, especially lower than 200nM, most preferably lower than 50nM.
Consider that it suppresses the ability of SGLT activity, compound of the present invention and corresponding pharmacologically acceptable salt thereof are suitable for treatment and/or prophylactic treatment is all by suppressing illness or the disease of SGLT active (especially for SGLT-2 is active) impact.Therefore, compound of the present invention is particularly suited for prevention or treatment disease, especially be metabolic disturbance or illness, for example 1 type and diabetes B, diabetic complication (retinopathy for example, ephrosis or neuropathy, diabetic foot, ulcer, macroangiopathy), metabolic acidosis or ketoacidosis, reactive hypoglycemia disease, hyperinsulinemia (hyperinsulinaemia), impaired glucose metabolism, insulin resistant, metabolism syndrome, the hyperlipemia of different causes, atherosclerosis and relative disease, fat, hypertension, chronic heart failure, oedema and hyperuricemia.These materials are also suitable for preventing beta cell to degenerate, for example apoptosis of pancreatic beta cell or necrosis.These materials are also suitable for improving or recovering the functional of pancreatic cell, and also increase quantity and the size of pancreatic beta cell.Compound of the present invention also can be used as diuretic(s) or hypotensive agent, and is suitable for prevention and treatment acute renal failure.
By administration compound of the present invention, can reduce or suppress fat abnormal accumulation in liver.Therefore; according to a further aspect in the invention; provide a kind of for preventing, slow down, postpone or treating owing to having disease that in this patient body needing, liver fat abnormal accumulation causes or the method for illness, the method is characterized in that administration compound of the present invention or pharmaceutical composition.Fatty liver or the poisoning fatty liver of the fatty liver that is especially selected from common fats liver, non-alcoholic fatty liver disease (NAFL), nonalcoholic steatohepatitis (NASH), supernutrition induction owing to disease or the illness of the abnormal accumulation of liver fat, diabetes fatty liver, alcohol induction.
Particularly, compound of the present invention, comprises acceptable salt on its physiology, is suitable for prevention or treatment diabetes, is especially 1 type and diabetes B and/or diabetic complication.
In addition, compound of the present invention is particularly suited for prevention or treats overweight, fat (comprising that I level, II level and/or III level are fat), internal organ obesity and/or abdominal obesity.
Realize treatment or prevent the required dosage of corresponding activity conventionally to depend on character and severity and medication and the frequency of compound, patient, disease or the illness of administration, and being determined by patient's doctor.Advantageously, by intravenous route dosage, can be 1 to 100mg, be preferably 1 to 30mg, and be 1 to 1000mg by oral route, be preferably 1 to 100mg, in each situation, administration every day is 1 to 4 time.For this purpose, optionally with other active substances, with the conventional carrier of one or more inertia and/or thinner, for example, with W-Gum, lactose, glucose, Microcrystalline Cellulose, Magnesium Stearate, polyvinylpyrrolidone, citric acid, tartrate, water, water/ethanol, water/glycerine, water/Sorbitol Powder, water/polyoxyethylene glycol, propylene glycol, cetostearyl alcohol, carboxymethyl cellulose or for example fatty substance or its suitable mixture of tristearin come together to prepare compound of the present invention, to produce conventional Gai Lun (galenic) preparation, common or coated tablet for example, capsule, powder agent, suspensoid or suppository.
Compound of the present invention also can be combined with other active substances, is particularly useful for treatment and/or prevents above-mentioned disease or illness.Other active substances that are suitable for these combinations comprise (for example), and those strengthen SGLT antagonist of the present invention for the active substance of mentioning the therapeutic action of one of indication and/or the dosage of SGLT antagonist of the present invention being minimized.The therapeutical agent that is suitable for this combination comprises (for example) antidiabetic, N1,N1-Dimethylbiguanide for example, sulfourea (Glyburide for example, tolbutamide (tolbutamide), glimepiride (glimepiride)), nateglinide (nateglinide), repaglinide (repaglinide), thiazolidinedione (rosiglitazone (rosiglitazone) for example, pioglitazone (pioglitazone)), PPAR-γ-agonist (for example GI262570) and antagonist, PPAR-γ/alpha modulators (for example KRP297), alpha-glucosidase inhibitor (acarbose (acarbose) for example, voglibose (voglibose)), DPPIV inhibitor (LAF237 for example, MK-431), α 2-antagonist, Regular Insulin and insulin analog, GLP-1 and GLP-1 analogue (for example Ai Shengding-4 (exendin-4)) or dextrin (amylin).Catalogue also comprises Protein-tyrosine-phosphatase 1 inhibitor, and it removes the material that regulates (deregulated) glucose to produce in liver for impact, for example G-6-Pase or fructose-1,6-bisphosphatase, phosphoric acid ester glucosylation enzyme inhibitors; Hyperglycemic-glycogenolytic factor (glucagon) receptor antagonist and phosphoenolpyruvate carboxykinase inhibitor, glycogen synthase kinase inhibitor or pyruvic acid dehydrogenation kinase inhibitor; Lipid lowering agent, for example HMG-CoA reductase inhibitor (for example Simvastatin (simvastatin), atorvastatin (atorvastatin)); The special class (fibrates) (for example bezafibrate (bezafibrate), fenofibrate (fenofibrate)) of shellfish; Nicotinic acid and derivative thereof; PPAR-alfa agonists; PPAR-delta agonists; ACAT inhibitor (for example avasimibe (avasimibe)) or for example cholesterol absorption inhibitor of ezetimibe (ezetimibe); The bile acide binding substance of QUESTRAN (cholestyramine) for example; Ileal bile acid transfer inhibitor; HDL rising compound, for example CETP inhibitor or ABC1 conditioning agent; Or treat fat active substance, for example sibutramine (sibutramine) or Pu Ta spit of fland, tetrahydrochysene Lip river (tetrahydrolipostatin), dexfenfluramine (dexfenfluramine), Dapiclermin (axokine); Cannabin(e) 1 receptor antagonist; MCH-1 receptor antagonist; MC4 receptor stimulant; NPY5 or NPY2 antagonist; Or β 3-agonist, for example SB-418790 or AD-9677 and 5HT2c receptor stimulant.
In addition, with for example, for affecting hypertension, chronic heart failure or atherosclerotic medicine (A-II antagonist or ACE inhibitor, ECE inhibitor, diuretic(s), beta blocker, Ca-antagonist, central action hypotensive agent, α-2-adrenoceptor antagonists, neutral endopeptidase inhibitor, anticoagulant and other drug or its combination) combination, be also suitable.The example of angiotonin II receptor antagonist is candesartan Cilexetil, Losartan Potassium (potassium losartan), Epr (eprosartan mesylate), valsartan (valsartan), telmisartan (telmisartan), Irb (irbesartan), EXP-3174, L-158809, EXP-3312, olmesartan medoxomill (olmesartan), medoxomil, Tasosartan (tasosartan), KT-3-671, GA-0113, RU-64276, EMD-90423, BR-9701 etc.Angiotonin II receptor antagonist is preferably used for treatment or preventing hypertension and diabetic complication, conventionally combines with the diuretic(s) of for example hydrochlorothiazide (hydrochlorothiazide).
Be suitable for treatment or prevention gout with the combination of uric acid synthetic inhibitor or uricosuric agent (uricosuric).
Can be used for treatment or prevent diabetes complication with the combination of GABA-receptor antagonist, Na-channel blocker, topiramate (topiramat), inhibitors of protein kinase C, advanced glycation endoproducts inhibitor or aldose reductase inhibitor.
The dosage of useful aforesaid combination collocation thing be common recommended lowest dose level 1/5 until conventionally 1/1 of institute's recommended dose.
Therefore, in another aspect, the present invention relates to the compound of the present invention of at least one above-mentioned active substance combination as combination collocation thing or the physiology of this compound on acceptable salt in preparation, be suitable for treatment or prevention can be by suppressing the purposes in the disease of sodium dependent glucose cotransporter SGLT impact or the pharmaceutical composition of illness.These diseases are preferably metabolic trouble, especially above one of listed disease or illness, more particularly diabetes or diabetic complication.
Use acceptable salt on compound of the present invention or its physiology to occur with another active substance combination simultaneously or at staggered time, but especially within the short timed interval, occur.If administration simultaneously, gives patient together by two kinds of active substances; And if at staggered time, use, be less than or equal to 12 hours, but especially by two kinds of active substances, giving patient being less than or equal in time of 6 hours.
Therefore, in another aspect, the present invention relates to pharmaceutical composition, acceptable salt and at least one above-mentioned active substance as mix and match thing on its physiology that comprises compound of the present invention or this compound, optionally together with one or more inert support and/or thinner.
Therefore, for example, on the physiology that pharmaceutical composition of the present invention comprises compound of the present invention or this compound acceptable salt and at least one angiotonin II receptor antagonist optionally with the mixing of one or more inert support and/or thinner.
On compound of the present invention or its physiology acceptable salt and treat with other active substances of its combination can together be present in a kind of preparation, for example tablet or capsule, or be present in dividually in two kinds of identical or different preparations, for example, as so-called parts test kit (kit-of-parts).
And hereinafter, in each situation, in structural formula, clearly do not represent the H atom of hydroxyl above.Following embodiment is intended to the present invention is described and does not limit the present invention.Term " room temperature " and " surrounding temperature " replaceable use and represent the temperature of approximately 20 ℃.
Use following abbreviation:
DMF dimethyl formamide
NMP METHYLPYRROLIDONE
THF tetrahydrofuran (THF)
The preparation of initial compounds:
Example I
The iodo-benzene of the bromo-3-hydroxymethyl-1-of 4-
Oxalyl chloride (13.0mL) is added into the iodo-phenylformic acid of the bromo-5-of 2-in CH
2cl
2(200mL) in the ice-cold solution in.Add DMF (0.2mL), and solution is at room temperature stirred 6 hours.Then under reduced pressure concentrate and resistates is dissolved in THF (100mL).Cooling gained solution and add LiBH by part in ice bath
4(3.4g).Remove cooling bath and mixture is stirred 1 hour under room temperature.With THF diluted reaction mixture and with the acid treatment of 0.1M salt.Follow separated organic layer and with ethyl acetate aqueous layer extracted.Dry (Na
2sO
4) through the organic layer of merging and in reducing pressure evaporating solvent to generate crude product.
Productive rate: 47.0g (theoretical value 99%)
Example II
The iodo-benzene of the bromo-3-chloromethyl-1-of 4-
Thionyl chloride (13mL) is added in the suspension of the 4-iodo-benzene of bromo-3-hydroxymethyl-1-(47.0g) in the methylene dichloride that contains DMF (0.1mL) (100mL).Mixture is stirred 3 hours at ambient temperature.Then under reduced pressure remove solvent and excess reagent.With methyl alcohol wet-milling resistates and dry.
Productive rate: 41.0g (theoretical value 82%)
EXAMPLE III
The iodo-3-phenoxymethyl-benzene of the bromo-1-of 4-
The phenol (13g) being dissolved in 4M KOH solution (60mL) is added in the 4-being dissolved in acetone (50mL) the iodo-benzene of bromo-3-chloromethyl-1-(41.0g).Add NaI (0.5g) and gained mixture is stirred and spent the night at 50 ℃.Then add water and extract gained mixture with ethyl acetate.Dry extract and vapourisation under reduced pressure solvent through merging.By silica gel chromatography purifying resistates (cyclohexane/ethyl acetate 19:1).
Productive rate: 38.0g (theoretical value 79%)
EXAMPLE IV
(the chloro-phenyl of the bromo-2-of 5-)-(4-methoxyl group-phenyl)-ketone
In the mixture of the chloro-phenylformic acid of the bromo-2-of 5-that 38.3mL oxalyl chloride and 0.8mL dimethyl formamide are added into 100g in 500mL methylene dichloride.Reaction mixture is stirred 14 hours, then filtration and separated from all volatile components in rotary evaporator.Resistates is dissolved in 150mL methylene dichloride, gained solution is cooled to-5 ℃, and add 46.5g methyl-phenoxide.Then portion-wise addition 51.5g aluminum chloride is so that temperature is no more than 5 ℃.By in 1 to 5 ℃ of solution, stir 1 hour and then incline to trash ice.Separated organic phase, and with dichloromethane extraction water.With 1M salt acid elution ECDC organic phase, 1M sodium hydroxide solution (2 times) and salt water washing ECDC also organic phase also.Then through dried over sodium sulfate organic phase, remove solvent and by resistates from ethyl alcohol recrystallization.
Productive rate: 86.3g (theoretical value 64%)
Mass spectrum (ESI
+): m/z=325/327/329 (Br+Cl) [M+H]
+
EXAMPLE V
The chloro-3-of the bromo-4-of 1-(4-methoxyl group-benzyl)-benzene
86.2g (the chloro-phenyl of the bromo-2-of 5-)-(4-methoxyl group-phenyl)-ketone and the solution of 101.5mL triethyl-silicane in 75mL methylene dichloride and 150mL acetonitrile are cooled to 10 ℃.Then follow stirring, add 50.8mL second boron-trifluoride etherate so that temperature is no more than 20 ℃.Solution is stirred 14 hours at ambient temperature, add again subsequently 9mL triethyl silicane and 4.4mL boron-trifluoride etherate.Solution stirred at 45-50 ℃ to 3 hour period again and be then cooled to surrounding temperature.Add the solution of 28g potassium hydroxide in 70mL water and gained mixture is stirred 2 hours.Separated organic phase and water being extracted 3 times again with Di Iso Propyl Ether.With 2M potassium hydroxide solution by the organic phase washed twice merging and with salt water washing once, and then through dried over sodium sulfate.After evaporating solvent, with washing with alcohol resistates and dry at 60 ℃.
Productive rate: 50.0g (theoretical value 61%)
Mass spectrum (ESI
+): m/z=310/312/314 (Br+Cl) [M+H]
+
Example VI
4-(the chloro-benzyl of the bromo-2-of 5-)-phenol
The solution of the chloro-3-of the bromo-4-of the 1-of cooling 14.8g (4-methoxyl group-benzyl)-benzene in 150mL methylene dichloride in ice bath.The 1M solution of the boron tribromide that adds 50mL in methylene dichloride and gained solution is stirred 2 hours at ambient temperature.Then cooling solution and dropwise add unsaturated carbonate aqueous solutions of potassium in ice bath again.The 1M aqueous hydrochloric acid of take is at ambient temperature adjusted to pH value as 1 by mixture, separated organic phase and with ethyl acetate aqueous phase extracted 3 times.Organic phase through dried over sodium sulfate through merging and remove solvent completely.
Productive rate: 13.9g (theoretical value 98%)
Mass spectrum (ESI
-): m/z=295/297/299 (Br+Cl) [M-H]
-
Example VII A
[4-(the chloro-benzyl of the bromo-2-of 5-)-the phenoxy group]-tertiary butyl-dimethyl-silicomethane
The 4-of cooling 13.9g in ice bath (the chloro-benzyl of the bromo-2-of the 5-) solution of-phenol in 140mL methylene dichloride.Then make an addition to the 7.54g tertiary butyl dimethylsilane chlorine in 20mL methylene dichloride, then add the 4-dimethylamino pyridine of 9.8mL triethylamine and 0.5g.Gained solution is stirred at ambient temperature to 16h and then with 100mL methylene dichloride, dilutes.With 1M aqueous hydrochloric acid, wash organic phase 2 times, and with sodium bicarbonate aqueous solution washing 1 time and then through dried over sodium sulfate.After removing solvent, via filtered through silica gel resistates (cyclohexane/ethyl acetate 100:1).
Productive rate: 16.8g (theoretical value 87%)
Mass spectrum (EI): m/z=410/412/414 (Br+Cl) [M]
+
Example VII A I
The bromo-4-of 1-(1-methoxyl group-D-glucopyranose-1-yl)-2-(phenoxymethyl)-benzene
2M solution by iPrMgCl in THF (11mL) is added in the anhydrous LiCl (0.47g) being suspended in THF (11mL).At room temperature stir the mixture until all LiCl all dissolve.This solution is dropwise added under argon atmospher and is cooled in the iodo-3-phenoxymethyl-benzene of the bromo-1-of 4-(8.0g) of-60 ℃ solution in tetrahydrofuran (THF) (40mL).By solution temperature to-40 ℃ and then make an addition to 2,3,4 in tetrahydrofuran (THF) (5mL), 6-tetra--O-(trimethyl silyl)-D-grape pyrone (10.7g, 90% is pure).By gained solution in cooling bath temperature to-5 ℃ and stir again at this temperature 30 minutes.Add NH
4the Cl aqueous solution and with ethyl acetate extraction gained mixture.Through dried over sodium sulfate, through the organic extract of merging and in decompression, go down to desolventize.Resistates is dissolved in methyl alcohol (80mL) and with methylsulfonic acid (0.6mL) and is processed.After reaction soln stirred at 35-40 ℃ spending the night, with solid NaHCO
3neutralization solution, and in the lower methyl alcohol of removing of decompression.With NaHCO
3the aqueous solution dilutes residue and extracts gained mixture with ethyl acetate.Extract through dried over sodium sulfate through merging and evaporating solvent are to generate crude product, and this crude product reduces without being further purified.
Productive rate: 7.8g (theoretical value 93%)
Example I X
The bromo-4-of 1-(2,3,4,6-, tetra--O-ethanoyl-D-glucopyranose-1-yl)-2-(phenoxymethyl)-benzene
With temperature, maintain-10 ℃ of following speed second boron-trifluoride etherate (4.9mL) is added into the bromo-4-of 1-(1-methoxyl group-D-glucopyranose-1-yl)-2-(phenoxymethyl)-benzene (8.7g) and triethyl silicane (9.1mL) being cooled in the solution of-20 ℃ in methylene dichloride (35mL) and acetonitrile (50mL).Through period of 1.5h, by gained solution temperature to 0 ℃, and then with sodium bicarbonate aqueous solution, process.Gained mixture is stirred 0.5 hour, remove organic solvent and with ethyl acetate extracted residues.Organic layer through dried over sodium sulfate through merging and removal solvent.Resistates is dissolved in methylene dichloride (50mL), connects and add diacetyl oxide (9.3mL), 4-dimethylamino pyridine (0.5g) and pyridine (9.4mL) in solution.Solution is stirred 1.5 hours at ambient temperature and then with methylene dichloride, dilute.With 1M hydrochloric acid by this solution washing 2 times and through dried over sodium sulfate.After removing solvent, resistates is to the product of colorless solid shape with generation from ethyl alcohol recrystallization.
Productive rate: 6.78g (theoretical value 60%)
Mass spectrum (ESI
+): m/z=610/612 (Br) [M+NH
4]
+
Embodiment X
2-(phenoxymethyl)-4-(2,3,4,6-, tetra--O-ethanoyl-D-glucopyranose-1-yl)-cyanobenzene
With argon, rinse zinc cyanide (1.0g), zinc (30mg), Pd are housed
2(dibenzalacetone)
3* CHCl
3(141mg) and Tetrafluoroboric acid tri-tert
(111mg) flask.Then add the solution of the bromo-4-of 1-(2,3,4,6-, tetra--O-ethanoyl-D-glucopyranose-1-yl)-2-(phenoxymethyl)-benzene (5.4g) in degassed NMP (12mL) and gained mixture is stirred 18 hours under room temperature.With after ethyl acetate dilution, filtering mixt and with sodium bicarbonate aqueous solution wash filtrate.Dry (sodium sulfate) organic phase and removal solvent.By resistates from ethyl alcohol recrystallization.
Productive rate: 4.10g (theoretical value 84%)
Mass spectrum (ESI
+): m/z=557[M+NH
4]
+
According to the following step, also obtain above-claimed cpd:
Stirring rod, the bromo-4-(2 of 1-will be housed; 3; 4,6-, tetra--O-ethanoyl-D-glucopyranose-1-yl) flask of-2-(phenoxymethyl)-benzene (14.7g), cupric cyanide (4.1g) and NMP (100mL) heats 8 hours under reflux temperature.After Yi Shui (600mL) dilution, precipitation separation, with water washing for several times and be dissolved in subsequently in ethyl acetate (200mL).Gained solution is filtered via the silica gel plug that uses ethyl acetate (300mL) as eluent.In the lower concentrated filtrate of decompression and resistates is dissolved in methylene dichloride (100mL) with the oxygen base of acetylize deprotection during cyanogenation again.Correspondingly, in turn add pyridine (4mL), 4-dimethylamino pyridine (0.3g) and diacetyl oxide (4.4mL).Gained solution is stirred 1 hour under room temperature.Then with methylene dichloride (50mL) diluted reaction mixture and with 1M aqueous hydrochloric acid washing 3 times, with sodium bicarbonate aqueous solution washing 1 time and with water washing 1 time.Dry (sodium sulfate) organic phase and removal solvent.By resistates from ethyl alcohol recrystallization.
Productive rate: 10.0g (theoretical value 75%)
Embodiment XI
2-brooethyl-4-(2,3,4,6-, tetra--O-ethanoyl-D-glucopyranose-1-yl)-cyanobenzene
33% solution by Hydrogen bromide in acetic acid (15mL) is added into 2-phenoxymethyl-4-(2; 3; 4,6-, tetra--O-ethanoyl-D-glucopyranose-1-yl) in-cyanobenzene (0.71g) and the solution of diacetyl oxide (0.12mL) in acetic acid (10ml).Gained solution is stirred 6 hours at 55 ℃ and follow cooling in ice bath.With cooling wet chemical neutralization reaction mixture, and with ethyl acetate extraction gained mixture.Through dried over sodium sulfate through merging organic extract and under reduced pressure removing solvent.Resistates is dissolved in ethyl acetate/hexanaphthene (1:5) and by filtering separation and precipitates and at 50 ℃, be dried to generate pure products.
Productive rate: 0.52g (theoretical value 75%)
Mass spectrum (ESI
+): m/z=543/545 (Br) [M+NH
4]
+
Embodiment XII
The chloro-4-of 1-(β-D-glucopyranose-1-yl)-2-(4-hydroxybenzyl)-benzene
[4-(the chloro-benzyl of the bromo-2-of 5-)-the phenoxy group]-tertiary butyl-dimethyl-silane solution in 42mL anhydrous diethyl ether of 4.0g is cooled to-80 ℃ under argon.1.7M ice-cold (approximately-50 ℃) solution by 11.6mL tert-butyl lithium in pentane is slowly added in cooling solution and then solution is stirred 30 minutes at-80 ℃.Then through with the cooling transfer pin of dry ice, this solution being dropwise added into 2,3,4 of 4.78g, in the solution of 6-tetra--O-(trimethyl silyl)-D-glucopyranose ketone being cooled in 38mL ether-80 ℃.Gained solution is stirred 3 hours at-78 ℃.Then add the solution of 1.1mL methylsulfonic acid in 35mL methyl alcohol and gained reaction soln is stirred 16 hours at ambient temperature again.Then with solid sodium bicarbonate neutralization solution, add ethyl acetate and concentrated gained solution under decompression.Sodium bicarbonate aqueous solution is added in the surplus solution with ethyl acetate extraction 4 times.Through dried over sodium sulfate through merging organic phase and evaporating solvent.Resistates is dissolved in 30mL acetonitrile and 30mL methylene dichloride and by gained solution and is cooled to-10 ℃.After adding 4.4mL triethyl silicane, dropwise add 2.6mL boron-trifluoride etherate so that temperature is no more than-5 ℃.After interpolation completes, by-5 to-10 ℃ of reaction solns, stir again 5 hours, and then by adding sodium bicarbonate aqueous solution, end.Separated organic phase and with ethyl acetate aqueous phase extracted 4 times.Organic phase through dried over sodium sulfate through merging, removes solvent and passes through silica gel column chromatography (methylene chloride/methanol) purifying resistates.The product then obtaining is isomer mixture, this mixture can by the diacetyl oxide with in methylene dichloride, pyridine and 4-dimethylamino pyridine carry out full acetylated hydroxyl and by gained acetylate from ethyl alcohol recrystallization and separation.The pure acetylize β-product (from the precipitation of ethanolic soln) so obtaining by remove ethanoyl with 4M potassium hydroxide solution in methyl alcohol changes into title product.
Productive rate: 1.6g (theoretical value 46%)
Mass spectrum (ESI
+): m/z=398/400 (Cl) [M+NH
4]
+
Embodiment XIII
The chloro-2-of 1-(4-cyclopentyloxy benzyl)-4-(β-D-glucopyranose-1-yl)-benzene
0.16mL iodo pentamethylene is added in the chloro-4-of 1-(β-D-glucopyranose-1-yl)-2-(4-the hydroxybenzyl)-benzene and the mixture of 0.4g cesium carbonate in 2.5mL dimethyl formamide of 0.25g.Mixture is stirred 4 hours at 45 ℃, add again subsequently 0.1g cesium carbonate and 0.05ml iodo pentamethylene.After stirring again 14 hours at 45 ℃, add sodium chloride aqueous solution and extract gained mixture with ethyl acetate.Through dried over sodium sulfate organic phase, remove solvent and use silica gel (methylene chloride/methanol 1:0->5:1) purifying resistates.
Productive rate: 0.23g (theoretical value 78%)
Mass spectrum (ESI
+): m/z=466/468 (Cl) [M+NH
4]
+
Be similar to embodiment XIII and obtain following compounds:
(1) the chloro-4-of 1-(β-D-glucopyranose-1-yl)-2-[4-((S)-tetrahydrofuran (THF)-3-base oxygen base)-benzyl]-benzene
(S)-toluene-4-sulfonic acid tetrahydrofuran (THF)-3-base ester of usining reacts as coupling collocation thing.
Mass spectrum (ESI
+): m/z=451/453 (Cl) [M+H]
+
Embodiment XIV
The chloro-4-of 1-(β-D-glucopyranose-1-yl)-2-[4-(trifluoromethyl sulfonyl oxygen base)-benzyl]-benzene
The 4-dimethylamino pyridine of 10mg is added into the N of the chloro-4-of 1-(β-D-glucopyranose-1-yl)-2-(4-hydroxybenzyl)-benzene, 0.21ml triethylamine and the 0.39g of 0.38g, in the N-pair-solution of (trifluoromethane sulfonyl group)-aniline in 10ml anhydrous methylene chloride.Solution is stirred 4 hours at ambient temperature, and then merge with salt solution.With ethyl acetate extraction gained mixture, through dried over sodium sulfate organic extract, and remove solvent.By silica gel column chromatography (methylene chloride/methanol is 1:0->4:1) purifying resistates.
Productive rate: 0.33g (theoretical value 64%)
Mass spectrum (ESI
+): m/z=530/532 (Cl) [M+NH
4]
+
Be similar to embodiment XIV and obtain following compounds:
(1) 1-cyano group-4-(β-D-glucopyranose-1-yl)-2-[4-(trifluoromethyl sulfonyl oxygen base)-benzyl]-benzene
Mass spectrum (ESI
+): m/z=504[M+H]
+
Embodiment XV
The chloro-4-of 1-(2,3,4,6-, tetra--O-ethanoyl-β-D-glucopyranose-1-yl)-2-[4-(trifluoromethyl sulfonyl oxygen base)-benzyl]-benzene
The chloro-4-of 1-(β-D-glucopyranose-1-yl)-2-[4-(trifluoromethyl sulfonyl oxygen base)-benzyl to 5.6g) in the solution of-benzene in 75mL methylene dichloride, add successively the 4-dimethylamino pyridine of 7mL pyridine, 7.8mL diacetyl oxide and 0.12g.Solution is stirred 1 hour at ambient temperature.After adding 50mL water, gained mixture is stirred 5 minutes again.Separated organic phase and with 1M aqueous hydrochloric acid and sodium bicarbonate aqueous solution washing.After dried over mgso and evaporation organic solvent, generate the product of the solid that is white in color.
Productive rate: 7.0g (theoretical value 94%)
Mass spectrum (ESI
+): m/z=698/700 (Cl) [M+NH
4]
+
Be similar to embodiment XV, obtain following compounds:
(1) 1-cyano group-4-(2,3,4,6-, tetra--O-ethanoyl-β-D-glucopyranose-1-yl)-2-[4-(trifluoromethyl sulfonyl oxygen base)-benzyl]-benzene
Mass spectrum (ESI
+): m/z=689[M+NH
4]
+
Embodiment XVI
The chloro-2-of 1-(4-ethynyl-benzyl)-4-(β-D-glucopyranose-1-yl)-benzene
By 25mg cupric iodide, 44mg two-(triphenyl phosphine)-palladium chloride, 0.30ml triethylamine and final 0.14ml trimethyl silyl acetylene is added into the chloro-4-of 1-(β-D-glucopyranose-1-yl)-2-[4-(trifluoromethyl sulfonyl oxygen the base)-benzyl of 0.32g under argon) in the solution of-benzene in 3ml dimethyl formyl.Flask is closely sealed and mixture is stirred 8 hours at 90 ℃.Then add again 25mg two-(triphenyl phosphine)-palladium chloride and 0.1ml trimethyl silyl acetylene, and solution is stirred 10 hours at 90 ℃ again.Then add sodium bicarbonate aqueous solution, with ethyl acetate extraction gained mixture 3 times, and through dried over sodium sulfate the organic phase through merging.After evaporating solvent, resistates is dissolved in 5ml methyl alcohol and with 0.12g salt of wormwood and is merged.Mixture is stirred at ambient temperature to 1h and then with 1M hydrochloric acid, neutralizes.Then methyl alcohol is removed in evaporation, and resistates and salt solution are merged and extracted with ethyl acetate.Through the collected organic extract of dried over sodium sulfate and removal solvent.By silica gel column chromatography (methylene chloride/methanol 1:0->5:1) purifying resistates.
Productive rate: 0.095g (theoretical value 40%)
Mass spectrum (ESI
+): m/z=406/408 (Cl) [M+NH
4]
+
Embodiment XVII
The chloro-2-of 1-(4-ethyl-benzyl)-4-(β-D-glucopyranose-1-yl)-benzene
The chloro-2-of the 1-of 2.87g (4-ethynyl-benzyl)-4-(β-D-glucopyranose-1-yl)-benzene is dissolved in 10ml ethyl acetate and 5ml ethanol.Add palladium-carbon of 10% of 0.3g and gained mixture is spent the night in lower stirring of nitrogen atmosphere (1atm).Through diatomite filtration reaction mixture and filtrate is concentrated.By the upper purifying resistates of silica gel column chromatography (methylene chloride/methanol is 1:0->5:1).
Productive rate: 1.0g (theoretical value 34%)
Mass spectrum (ESI
+): m/z=410/412 (Cl) [M+NH
4]
+
Embodiment XVIII
The chloro-2-[4-of 1-((S)-tetrahydrofuran (THF)-3-base oxygen base)-benzyl]-4-(2,3,4,6-, tetra--O-ethanoyl-β-D-glucopyranose-1-yl) benzene
The chloro-4-of 1-(β-D-glucopyranose-1-yl)-2-[4-((S)-tetrahydrofuran (THF)-3-base oxygen base)-benzyl to 2.02g] add successively the 4-dimethylamino pyridine of 2.5mL pyridine, 2.8mL diacetyl oxide and 50mg in the solution of-benzene in 20mL methylene dichloride.Reaction soln is stirred 4 hours at ambient temperature.With 50mL methylene dichloride diluting soln, with the 1M salt acid elution 2 times of 50mL and with sodium hydrogen carbonate solution washing 1 time.After dried over sodium sulfate, evaporating solvent is to produce product.
Productive rate: 2.53g (theoretical value 91%)
Mass spectrum (ESI
+): m/z=642/644 (Cl) [M+Na]
+
Be similar to embodiment XVIII and obtain following compounds:
(1) the chloro-2-of 1-(4-ethyl-benzyl)-4-(2,3,4,6-, tetra--O-ethanoyl-β-D-glucopyranose-1-yl)-benzene
(2) the chloro-4-of 2-(4-acetoxyl group-benzyl)-1-(2,3,4,6-, tetra--O-ethanoyl-β-D-glucopyranose-1-yl)-benzene
Mass spectrum (ESI
+): m/z=608/610 (Cl) [M+NH
4]
+
(3) 1-cyano group-2-(4-methoxyl group-benzyl)-4-(2,3,4,6-, tetra--O-ethanoyl-β-D-glucopyranose-1-yl)-benzene
Mass spectrum (ESI
+): m/z=567[M+Na]
+
Embodiment XIX
The chloro-2-of 1-(4-methyl-benzyl)-4-(2,3,4,6-, tetra--O-ethanoyl-β-D-glucopyranose-1-yl)-benzene
By diisobutyl aluminium hydride (54 μ L, 1mol/l in toluene) under Ar atmosphere, be added into 1,1 '-bis-(diphenylphosphino) ferrocene-dichloro palladium (II) (22mg) in the mixture in THF (3mL) and cooling in ice bath.Mixture stirred in ice bath 0.5 hour and then add successively the chloro-4-of 1-(2,3,4,6-, tetra--O-ethanoyl-β-D-glucopyranose-1-yl)-2-[4-(trifluoromethyl sulfonyl oxygen base)-benzyl]-benzene (0.60g) and Me
2zn (0.88mL, the 1mol/L in toluene).Remove ice bath and mixture is heated 2.5 hours under refluxing.After being cooled to room temperature, adding 1M hydrochloric acid and gained mixture is extracted to gained mixture with ethyl acetate.Through the collected extract of dried over sodium sulfate and removal solvent.By silica gel column chromatography (methylene chloride/methanol is 1:0->2:1) purifying resistates.
Productive rate: 0.25g (theoretical value 52%)
Embodiment XX
The chloro-2-of 1-(4-cyano group-benzyl)-4-(2,3,4,6-, tetra--O-ethanoyl-β-D-glucopyranose-1-yl)-benzene
Four (triphenyl phosphine) palladium (0) (0.13g) is added into the chloro-4-(2 of 1-is housed under argon gas atmosphere; 3; 4,6-, tetra--O-ethanoyl-β-D-glucopyranose-1-yl)-2-[4-(trifluoromethyl sulfonyl oxygen base)-benzyl] in the flask of-benzene (0.80g) and zinc cyanide (0.14g).Mixture is stirred 3 hours at 100 ℃.After being cooled to room temperature, adding ethyl acetate and filter gained mixture, with NaHCO
3solution washing, dry (sodium sulfate), and remove solvent.By resistates from ethyl alcohol recrystallization.
Productive rate: 0.45g (theoretical value 69%)
Mass spectrum (ESI
+): m/z=580/582 (Cl) [M+Na]
+
Embodiment XXI
4-cyclopropyl-phenyl-boron dihydroxide
To in the hexane solution of 2.5M n-Butyl Lithium (14.5mL), dropwise be added in the bromo-4-cyclopropyl-benzene of 1-(5.92g) in THF (14mL) and toluene (50mL) that is cooled to-70 ℃.Gained solution is stirred 30 minutes at-70 ℃, add subsequently triisopropyl borate ester (8.5mL).By solution temperature to-20 ℃ and then process with 4M aqueous hydrochloric acid (15.5mL).By reaction mixture further temperature to room temperature and follow separated organic phase.With ethyl acetate, extract and be dried (sodium sulfate) through merging organic phase.Evaporating solvent and with the mixture debris of ether and hexanaphthene to generate the product that is colorless solid.
Productive rate: 2.92g (theoretical value 60%)
Mass spectrum (ESI
-): m/z=207 (Cl) [M+HCOO]
-
Be similar to embodiment XXI and obtain following compounds:
(1) 4-difluoro-methoxy-phenyl-boron dihydroxide
Mass spectrum (ESI
-): m/z=233 (Cl) [M+HCOO]
-
Be different from above-mentioned steps, with iPrMgCl, from the iodo-benzene of 4-difluoro-methoxy-1-, generate arylide and with boric acid trimethylammonium ester, catch this intermediate and prepare this compound.
(2) 4-difluoro-methoxy-phenyl-boron dihydroxide
Mass spectrum (ESI
+): m/z=172 (Cl) [M+H]
+
Be different from above-mentioned steps, use iPrMgCl generate arylide and with trimethyl borate, catch this intermediate and prepare this compound from the iodo-benzene of 4-difluoromethyl-1-(the diethyl amido sulfur trifluoride (DAST) being used in methylene dichloride is prepared from 4-benzaldehyde iodine).
Embodiment XXII
The bromo-4-cyano group-3-of 1-(4-methoxyl group-benzyl)-benzene
Temperature is remained on below 10 ℃, the mixture of N-methyl-pyrrolidin-2-one of the 1-fluoro-benzene of bromo-4-cyano group-3-of (4-methoxyl group-phenyl)-ethyl acetate of 25g, 27.4g and 20mL is slowly added in the 31.4g potassium tert.-butoxide in 130mL N-methyl-pyrrolidin-2-one.After at room temperature stirring 1h, add 100mL methyl alcohol and 137mL1M aqueous sodium hydroxide solution and mixture is stirred and spent the night under room temperature.Evaporation methyl alcohol part, with 1M aqueous sodium hydroxide solution alkalization resistates and with the extraction of the tertiary butyl-methyl ether.With 4M hydrochloric acid, carry out acidifying water and extract several times with ethyl acetate.The acetic acid ethyl ester extract of evaporation through merging and DMF and the 24.9g salt of wormwood together with 120mL heats 1 hour at 100 ℃ by resistates.With sodium bicarbonate aqueous solution diluted reaction mixture and with ethyl acetate extraction several times.The extract of evaporation through merging and by resistates from methanol crystallization.
Productive rate: 13g (theoretical value 33%)
Mass spectrum (ESI
+): m/z=319/321 (Br) [M+NH
4]
+
Be similar to embodiment XXII and obtain following compounds:
(1) the bromo-4-cyano group-3-of 1-(4-cyclopropyl-benzyl)-benzene
Mass spectrum (ESI
+): m/z=329/331 (Br) [M+NH
4]
+
Synthetic for the preparation of the required phenyl acetic acid derivatives of this compound according to later step embodiment XXIII.
Embodiment XXIII
4-cyclopropyl-Phenylacetic acid ethylester
According to Tetrahedron Lett.2002,43,6987-6990, is used in the Tetrafluoroboric acid thricyclohexyl in toluene and water
acid chloride, potassiumphosphate are prepared by the bromo-Phenylacetic acid ethylester of 4-by transition metal-catalyzed lower and cyclopropylboronic acid coupling.
Mass spectrum (ESI
+): m/z=205[M+H]
+
Embodiment XXIV
1-cyano group-4-(β-D-glucopyranose-1-yl)-2-(4-methoxy-benzyl)-benzene
To stirring rod be housed and be dissolved in 1-bromo-4-cyano group-3-(4-methoxyl group-benzyl)-benzene (9.90g) in anhydrous THF (120mL) and the flask that remains under argon atmospher is cooled to-87 ℃.Pre-cooled (approximately-70 ℃) solution by tert-butyl lithium in pentane (1.7M, 39mL) slowly adds so far in solution and gained solution is stirred 30 minutes at-87 ℃.Then adding 2,3,4,6-, tetra--O-(trimethyl silyl)-D-glucopyranose ketone (16.5g) is dissolved in the solution in THF (80mL) and the solution of merging is stirred 1 hour at-75 ℃.With NH
4cl aqueous solution stopped reaction and with ethyl acetate extraction gained mixture.At dry (Na
2sO
4) organic extract and remove solvent after, resistates is dissolved in methyl alcohol (150mL) and adds methylsulfonic acid (5mL).Gained solution is stirred at 55 ℃ to 8 hours to generate required end group isomery (anomeric) configuration.After being cooled to Periodic Temperature, with solid sodium bicarbonate neutralization solution, and vapourisation under reduced pressure methyl alcohol.Salt solution is added in residue and with ethyl acetate extraction gained mixture.Dry (sodium sulfate) extract and evaporating solvent through merging.Resistates is dissolved in acetonitrile (50mL) and methylene dichloride (50mL) with reduction end group isomery carbon center.This solution being cooled to-20 ℃ and add triethyl silicane (16mL) afterwards, dropwise add boron trifluoride diethyl etherate compound (9.2mL).Reaction soln is slowly to warm in cooling bath to 0 ℃ and then by adding sodium bicarbonate aqueous solution stopped reaction.Separated organic phase and with ethyl acetate aqueous phase extracted.Dry (sodium sulfate) organic phase through merging, removes solvent and by silica gel column chromatography (methylene chloride/methanol is 1:0->9:1) purifying resistates.
Productive rate: 5.2g (theoretical value 41%)
Mass spectrum (ESI
+): m/z=403[M+NH
4]
+
Be similar to embodiment XXIV and obtain following compounds:
(1) 1-cyano group-2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranose-1-yl)-benzene
Mass spectrum (ESI
-): m/z=413[M+H]
+
Oxygen functional group's reduction of advantageously, muttering with protected piperazine on sugar ring in the end group isomery carbon center that synthesizes the suitable intermediate obtaining during this compound.Preferably protecting group be benzyl, to methoxy-benzyl, trimethyl silyl, triethyl silyl, tertiary butyl dimethylsilyl, tri isopropyl silane base and allyl group.
Embodiment XXV
1-cyano group-2-(4-cyclopropyl-benzyl)-4-(four-O-ethanoyl-β-D-glucopyranose-1-yl)-benzene
To stirring rod, 4-(2 are housed; 3; 4,6-, tetra--O-ethanoyl-D-glucopyranose-1-yl)-2-(4-trimethyl fluoride sulfonyl oxygen base-benzyl)-cyanobenzene (4.4g), degassed toluene (12mL) and de aerated water (8mL) and remain on flask under argon atmospher and add cyclopropylboronic acid (0.20g), potassiumphosphate (5.0g), tricyclohexyl phosphine (0.19g) and acid chloride (II) (76mg).Mixture is stirred 6 hours at 110 ℃, after every 1 hour, add cyclopropylboronic acid (5x0.20g) simultaneously.After being cooled to room temperature, with sodium bicarbonate aqueous solution, diluting mixture and extract with ethyl acetate.Dry (sodium sulfate) is through the extract of merging and in reducing pressure down to desolventize.Through silica gel (cyclohexane/ethyl acetate is 20:1->1:1) residue of chromatography.
Productive rate: 3.2g (theoretical value 87%)
Mass spectrum (ESI
+): m/z=581[M+NH
4]
+
Embodiment XXVI
4-(1-hydroxyl-cyclopropyl)-phenyl-boron dihydroxide
3.0M solution by ethyl-magnesium-bromide in ether (7.6mL) is added into (2.2mL) being cooled in the stirred solution of-78 ℃ in ether (70mL) of titanium isopropylate (IV).Gained solution is stirred 1.5 hours at-78 ℃, add subsequently 4-(4,4,5,5-[1,3,2] dioxa boron Polymorphs-2-yl)-methyl benzoate (2.0g).By reaction mixture temperature to surrounding temperature and stir again 12 hours.Then add 1M aqueous hydrochloric acid and extract gained mixture with ethyl acetate.Dry (sodium sulfate) organic extract and evaporating solvent through merging.Resistates is dissolved in acetone (60mL), and adds the NH of 0.1M
4the OAc aqueous solution (50mL), adds NaIO then
4(2.3g).Gained reaction mixture is stirred 18 hours under room temperature.After removing acetone, with ethyl acetate extracted residues.Dry (sodium sulfate) extract and evaporating solvent through merging.By silica gel column chromatography (cyclohexane/ethyl acetate) purifying resistates.
Productive rate: 0.45g (theoretical value 33%)
Mass spectrum (ESI
-): m/z=223[M+HCOO]
-
The preparation of final compound:
Reference example 1
4-(β-D-glucopyranose-1-yl)-2-[4-((S)-tetrahydrofuran base-3-oxygen base)-benzyl]-cyanobenzene
By the chloro-2-[4-of the 1-of 1.00g ((S)-tetrahydrofuran base-3-oxygen base)-benzyl]-4-(2; 3; 4,6-, tetra--O-ethanoyl-β-D-glucopyranose-1-yl) the microwave oven heating at 220 ℃ of-benzene, 0.16g sodium cyanide and the mixture of 0.35g nickelous bromide in 2.5mL METHYLPYRROLIDONE is 15 minutes.After being cooled to room temperature, adding water and extract gained mixture with ethyl acetate.After dried over sodium sulfate and evaporating solvent, resistates is dissolved in 5mL methyl alcohol.Add the 4M potassium hydroxide aqueous solution of 4mL and reaction soln is stirred 3 hours at ambient temperature.With 1M hydrochloric acid neutralization solution and evaporation methyl alcohol.With ethyl acetate extracted residues, the extract through dried over sodium sulfate through merging, and go down to desolventize in decompression.By silica gel column chromatography (methylene chloride/methanol is 4:1) purifying resistates.
Productive rate: 0.35g (theoretical value 49%)
Mass spectrum (ESI
+): m/z=442[M+H]
+
Be similar to reference example 1, obtain the compound of embodiment 1,2,3 and 4:
Embodiment 1:2-(4-ethyl-benzyl)-4-(β-D-glucopyranose-1-yl)-cyanobenzene
Productive rate: 65% of theoretical value
Mass spectrum (ESI
+): m/z=401[M+NH
4]
+
Be similar to embodiment 6, use 4-ethylphenyl boric acid also can prepare this compound as coupling collocation thing.
Embodiment 2:4-(β-D-glucopyranose-1-yl)-2-(4-hydroxyl-benzyl)-cyanobenzene
According to above-mentioned steps, from the chloro-4-of 2-(4-acetoxyl group-benzyl)-1-(2,3,4,6-, tetra--O-ethanoyl-β-D-glucopyranose-1-yl)-benzene, prepare this compound.
Productive rate: 30% of theoretical value
Mass spectrum (ESI
+): m/z=389[M+NH
4]
+
Also by full acetylated 2-(4-methoxyl group-benzyl)-4-(β-D-glucopyranose-1-yl)-cyanobenzene, then with boron tribromide cracking ether and deacetylation, obtain this compound.
Embodiment 3:4-(β-D-glucopyranose-1-yl)-2-(4-methyl-benzyl)-cyanobenzene
Productive rate: 59% of theoretical value
Mass spectrum (ESI
+): m/z=387[M+NH
4]
+
Be similar to embodiment 6, use 4-aminomethyl phenyl boric acid also can prepare this compound as coupling collocation thing.
Embodiment 4:2-(4-cyano group-benzyl)-4-(β-D-glucopyranose-1-yl)-cyanobenzene
Productive rate: 58% of theoretical value
Mass spectrum (ESI
+): m/z=398[M+NH
4]
+
Embodiment 5
4-(β-D-glucopyranose-1-yl)-2-(4-methoxy ethoxy-benzyl)-cyanobenzene
2-bromo-ethyl-methyl ether (85 μ l) is added in 4-(β-D-glucopyranose-1-yl)-2-(4-hydroxybenzyl)-cyanobenzene (0.30g) and the mixture of cesium carbonate (0.39g) in 3mL dimethyl formamide.Mixture is stirred 16 hours at 80 ℃, add subsequently water and salt solution.With ethyl acetate extraction gained mixture, the extract through dried over sodium sulfate through merging, and go down to desolventize in decompression.By silica gel column chromatography (methylene chloride/methanol is 1:0->5:1) purifying resistates.
Productive rate: 0.19g (theoretical value 49%)
Mass spectrum (ESI
+): m/z=430[M+H]
+
Embodiment 6
4-(β-D-glucopyranose-1-yl)-2-(4-trifluoromethoxy-benzyl)-cyanobenzene
In the flask of filling through argon gas, pack 2-brooethyl-4-(2 into; 3; 4,6-, tetra--O-ethanoyl-D-glucopyranose-1-yl) the 3:1 mixture (4mL) of-cyanobenzene (0.25g), 4-trifluoromethoxy-phenyl-boron dihydroxide (0.20g), salt of wormwood (0.26g) and degassed acetone and water.Mixture is stirred 5 minutes under room temperature, in ice bath, it is cooling subsequently.Then add palladium chloride (5mg) and reaction mixture is stirred 16 hours at ambient temperature.Then with salt solution, dilute mixture and extract with ethyl acetate.Through dried over sodium sulfate, through the extract of merging and in decompression, go down to desolventize.Resistates is dissolved in methyl alcohol (9mL) and with 4M potassium hydroxide aqueous solution (1mL) and is processed.Gained solution is stirred at ambient temperature to 1h and then with 1M hydrochloric acid, neutralizes.Evaporation methyl alcohol, and dilute resistates and extract with ethyl acetate with salt solution.Through the collected organic extract of dried over sodium sulfate and removal solvent.Through silica gel (methylene chloride/methanol 1:0->8:1) residue of chromatography.
Productive rate: 0.145g (theoretical value 69%)
Mass spectrum (ESI
+): m/z=457[M+NH
4]
+
In some cases, by increasing productive rate with 1.5 to 2.0 boric acid of equivalent and the alkali of proportional increase.
Be similar to embodiment 6 and obtain following compounds:
Embodiment 7:4-(β-D-glucopyranose-1-yl)-2-(4-trifluoromethyl-benzyl)-cyanobenzene
Productive rate: 47% of theoretical value
Mass spectrum (ESI
+): m/z=441[M+NH
4]
+
Embodiment 8:4-(β-D-glucopyranose-1-yl)-2-(4-sec.-propyl-benzyl)-cyanobenzene
Productive rate: 87% of theoretical value
Mass spectrum (ESI
+): m/z=415[M+NH
4]
+
Embodiment 9:4-(β-D-glucopyranose-1-yl)-2-(the 4-tertiary butyl-benzyl)-cyanobenzene
Productive rate: 66% of theoretical value
Mass spectrum (ESI
+): m/z=429[M+NH
4]
+
Embodiment 10:4-(β-D-glucopyranose-1-yl)-2-(4-trimethyl silyl-benzyl)-cyanobenzene
Productive rate: 70% of theoretical value
Mass spectrum (ESI
+): m/z=445[M+NH
4]
+
Embodiment 11:4-(β-D-glucopyranose-1-yl)-2-(4-methylthio group-benzyl)-cyanobenzene
Productive rate: 47% of theoretical value
Mass spectrum (ESI
+): m/z=419[M+NH
4]
+
Embodiment 12:4-(β-D-glucopyranose-1-yl)-2-[4-(3-methyl-Ding-1-yl)-benzyl]-cyanobenzene
Productive rate: 69% of theoretical value
Mass spectrum (ESI
+): m/z=443[M+NH
4]
+
Embodiment 13:2-(the fluoro-benzyl of 4-)-4-(β-D-glucopyranose-1-yl)-cyanobenzene
Productive rate: 34% of theoretical value
Mass spectrum (ESI
+): m/z=391[M+NH
4]
+
Embodiment 14:2-(the chloro-benzyl of 4-)-4-(β-D-glucopyranose-1-yl)-cyanobenzene
Productive rate: 32% of theoretical value
Mass spectrum (ESI
+): m/z=407/409 (Cl) [M+NH
4]
+
Embodiment 15:2-(4-difluoro-methoxy-benzyl)-4-(β-D-glucopyranose-1-yl)-cyanobenzene
Productive rate: 32% of theoretical value
Mass spectrum (ESI
+): m/z=439[M+NH
4]
+
Embodiment 16:2-(4-difluoromethyl-benzyl)-4-(β-D-glucopyranose-1-yl)-cyanobenzene
Productive rate: 65% of theoretical value
Mass spectrum (ESI
+): m/z=423[M+NH
4]
+
Embodiment 17:2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranose-1-yl)-cyanobenzene
Mass spectrum (ESI
+): m/z=413[M+NH
4]
+
According to embodiment 6, use 4-cyclopropyl-phenyl-boron dihydroxide to obtain this compound as coupling collocation thing.
Productive rate: 83% of theoretical value
Or, described in embodiment XXIV (1), obtain this compound.
By using the following step also to obtain the compound of embodiment 17:
With potassium hydroxide aqueous solution (4mol/l; 5mL) process 2-(4-cyclopropyl-benzyl)-4-(2; 3,4,6-, tetra--O-ethanoyl-D-glucopyranose-1-yl) solution of-cyanobenzene (0.80g) in methyl alcohol (5mL) and THF (5mL).Reaction soln is stirred at ambient temperature to 1h and then with 1M hydrochloric acid, neutralizes.Evaporate organic solvent and dilute resistates with salt solution, and extract with ethyl acetate.Dry (sodium sulfate) organic extract and removal solvent.Through silica gel (methylene chloride/methanol is 1:0->9:1) residue of chromatography.
Productive rate: 0.54g (theoretical value 96%)
Embodiment 18:2-(4-cyclobutyl-benzyl)-4-(β-D-glucopyranose-1-yl)-cyanobenzene
According to embodiment 6, use 4-cyclobutyl boric acid (can be similar to embodiment XXI obtains) to obtain this compound as coupling collocation.
Productive rate: 51% of theoretical value
Mass spectrum (ESI
-): m/z=427[M+NH
4]
+
Embodiment 19:4-(β-D-glucopyranose-1-yl)-2-(4-third-1-base-benzyl)-cyanobenzene
Productive rate: 64% of theoretical value
Mass spectrum (ESI
+): m/z=415[M+NH
4]
+
Embodiment 20:4-(β-D-glucopyranose-1-yl)-2-[4-(1-hydroxyl-cyclopropyl)-benzyl)-cyanobenzene
According to embodiment 6, use 4-(1-hydroxyl-cyclopropyl)-phenyl-boron dihydroxide can obtain this compound as coupling collocation.
Embodiment 21
4-(β-D-glucopyranose-1-yl)-2-(the iodo-benzyl of 4-)-cyanobenzene
1M solution by iodine monochloride in methylene dichloride (0.9mL) is added in 4-(β-D-glucopyranose-1-yl)-2-(4-trimethyl silyl-benzyl)-cyanobenzene (0.26g) being dissolved in methylene dichloride (5mL).Solution is at room temperature stirred to 1h and then passes through to add Na
2s
2o
3the aqueous solution and NaHCO
3the aqueous solution is ended.Separated organic phase is separated and with ethyl acetate aqueous phase extracted.Organic phase through dried over sodium sulfate through merging and removal solvent.Through silica gel (methylene chloride/methanol is 1:0->8:1) residue of chromatography.
Productive rate: 0.15g (theoretical value 88%)
Mass spectrum (ESI
+): m/z=499[M+NH
4]
+
Be similar to embodiment 20 and can obtain following compounds:
(22) 2-(the bromo-benzyl of 4-)-4-(β-D-glucopyranose-1-yl)-cyanobenzene
Productive rate: 79% of theoretical value
Mass spectrum (ESI
+): m/z=451/453[M+NH
4]
+
According to the step of embodiment 20, use the ICl in bromine instead of methylene chloride to obtain this compound.
Embodiment 23
4-(β-D-glucopyranose-1-yl)-2-(4-pentafluoroethyl group-benzyl)-cyanobenzene
4-(2 will be housed; 3; 4,6-, tetra--O-ethanoyl-β-D-glucopyranose-1-yl) flask of-2-(the iodo-benzyl of 4-)-cyanobenzene (0.16g), pentafluoroethyl group trimethyl silane (0.14g), KF (43mg), CuI (0.16g), DMF (2mL) and the charging of Ar atmosphere heats 24 hours at 60 ℃.Then add NaHCO
3the aqueous solution and with ethyl acetate extraction gained mixture.Organic phase through dried over sodium sulfate through merging and removal solvent.Resistates is dissolved in methyl alcohol (8mL) and with 4M KOH solution (0.8mL) and is processed.Solution stirred under room temperature to 1h and follow with NaHCO
3aqueous solution dilution.After the lower removal of decompression methyl alcohol, with ethyl acetate extracted residues, be dried the organic extract through merging and remove solvent.Through silica gel (methylene chloride/methanol is 1:0->8:1) residue of chromatography.
Productive rate: 0.08g (theoretical value 69%)
Mass spectrum (ESI
+): m/z=491[M+NH
4]
+
Embodiment 24
4-(β-D-glucopyranose-1-yl)-2-(4-methylsulfinyl-benzyl)-cyanobenzene
The aqueous solution of 35% hydrogen peroxide (48 μ L) is added as in the 4-in HFIP (2mL) (β-D-glucopyranose-1-yl)-2-(4-methylthio group-benzyl)-cyanobenzene (83mg).Gained solution is stirred at ambient temperature to 1h and then passes through to add Na
2s
2o
3the aqueous solution and NaHCO
3the aqueous solution is ended.Separated organic phase and with ethyl acetate aqueous phase extracted.Organic phase through dried over sodium sulfate through merging and removal solvent.Through silica gel (methylene chloride/methanol is 1:0->5:1) residue of chromatography.
Productive rate: 24mg (theoretical value 28%)
Mass spectrum (ESI
+): m/z=418[M+H]
+
Embodiment 25
4-(β-D-glucopyranose-1-yl)-2-(4-methyl sulphonyl-benzyl)-cyanobenzene
By 3-chloroperoxybenzoic acid (70%, 0.14g) be added in the 4-in methylene dichloride (2mL) cooling in ice bath (β-D-glucopyranose-1-yl)-2-(4-methylthio group-benzyl)-cyanobenzene (100mg).Remove cooling bath and gained solution is stirred 1 hour at ambient temperature.Add Na
2s
2o
3the aqueous solution and NaHCO
3after the aqueous solution, separated organic phase and will be with ethyl acetate aqueous phase extracted.Organic phase through dried over sodium sulfate through merging and removal solvent.Through silica gel (methylene chloride/methanol is 1:0->8:1) residue of chromatography.
Productive rate: 68mg (theoretical value 63%)
Mass spectrum (ESI
+): m/z=451[M+NH
4]
+
Be similar to above-described embodiment or the additive method known to document also can be prepared following compounds:
To describe the embodiment of some preparations now, wherein term " active substance " represents one or more compound of the present invention, comprises its prodrug or salt.As previously mentioned with a kind of other active substance combination in the situation that, term " active substance " also comprises other active substances.
Embodiment A
The tablet that contains 100mg active substance
Form:
1 tablet contains:
Preparation method:
Active substance, lactose and starch are mixed and moistening with polyvinylpyrrolidone aqueous solution homogeneous.After wet mixture being sieved (2.0mm screen size) and being dried at 50 ℃ in frame type (rack-type) moisture eliminator, it sieved again (1.5mm screen size) and add lubricant.Final mixture compressing tablet is formed to tablet.
Tablet weight: 220mg
Diameter: 10mm, two-sided, in both sides, portray and have indentation in a side.
Embodiment B
The tablet that contains 150mg active substance
Form:
1 tablet contains:
Preparation:
The active substance mixing with lactose, W-Gum and silicon-dioxide is wetting and by the sieve of 1.5mm screen size with the 20% polyvinylpyrrolidone aqueous solution.Make dry granules at 45 ℃ again pass identical sieve and mix with the Magnesium Stearate of specified quantitative.Mixture is pressed into tablet.
Tablet weight: 300mg
Diameter: 10mm is flat
Embodiment C
The hard capsule that contains 150mg active substance
Form:
1 capsule contains:
Preparation:
By active substance and mixed with excipients, the sieve by 0.75mm screen size and use suitable equipment evenly to mix.Final mixture is packed in the hard capsule of specification 1.
Capsule filler: about 320mg
Capsule shell: the hard capsule of specification 1.
Embodiment D
The suppository that contains 150mg active substance
Form:
1 suppository contains:
Preparation:
After the melting of suppository material, active substance is uniformly distributed in wherein, and by melt impouring cooling die.
Embodiment E
The ampoule that contains 10mg active substance
Form:
Active substance 10.0mg
0.01N hydrochloric acid is appropriate
Distilled water adds to 2.0ml
Preparation:
Active substance is dissolved in the HCl of 0.01N of necessary amounts, with salt, its grade is opened, sterile filtration and being transferred in 2ml ampoule.
Embodiment F
The ampoule that contains 50mg active substance
Form:
Active substance 50.0mg
0.01N hydrochloric acid is appropriate
Distilled water adds to 10.0ml
Preparation:
Active substance is dissolved in the HCl of 0.01N of necessary amounts, with salt, its grade is opened, sterile filtration and being transferred in 10ml ampoule.
Claims (12)
1. the cyanobenzene derivative being replaced by glucopyranose base of formula I; Comprise its tautomer, steric isomer or its mixture; And acceptable salt on physiology:
Wherein
R
3represent hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl group, sec.-propyl, butyl, sec-butyl, isobutyl-, the tertiary butyl, 3-methyl-Ding-1-base, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-hydroxyl-cyclopropyl, 1-hydroxyl-cyclobutyl, 1-hydroxyl-cyclopentyl, 1-hydroxyl-cyclohexyl, difluoromethyl, trifluoromethyl, pentafluoroethyl group, 2-hydroxyl-ethyl, hydroxymethyl, 3-hydroxyl-propyl, 2-hydroxy-2-methyl-propyl-1-base, 3-hydroxy-3-methyl-Ding-1-base, 1-hydroxyl-1-methyl-ethyl, 2, 2, the fluoro-1-hydroxyl-1-of 2-tri-methyl-ethyl, 2, 2, the fluoro-1-hydroxyl-1-of 2-tri-trifluoromethyl-ethyl, 2-methoxyl group-ethyl, 2-oxyethyl group-ethyl, hydroxyl, difluoro-methoxy, trifluoromethoxy, 2-methoxyl group-oxyethyl group, methylthio group, methylsulfinyl, methyl sulphonyl, ethyl sulfinyl, ethylsulfonyl, trimethyl silyl and cyano group,
Or derivatives thereof: wherein one or more hydroxyl of β-D-glucopyranose base is selected from (C
1-18alkyl) carbonyl, (C
1-18alkyl) oxygen base carbonyl, phenylcarbonyl group and phenyl-(C
1-3the group acidylate of alkyl)-carbonyl.
2. the cyanobenzene derivative being replaced by glucopyranose base as claimed in claim 1 or its physiologically acceptable salt, wherein the hydrogen atom of the hydroxyl O-6 of this β-D-glucopyranose base is through being selected from (C
1-8alkyl) carbonyl, (C
1-8alkyl) group displacement in oxygen base carbonyl and phenylcarbonyl group.
3. the physiologically acceptable salt that compound as claimed in claim 1 or 2 and mineral acid or organic acid form.
4. pharmaceutical composition, it comprises acceptable salt on compound as claimed in claim 1 or 2 or physiology as claimed in claim 3, and optionally one or more inert support and/or thinner.
5. at least one compound as claimed in claim 1 or 2 or physiology as claimed in claim 3, acceptable salt is suitable for treatment or prevention can be by the purposes suppressing in the disease of sodium dependent glucose cotransporter SGLT impact or the pharmaceutical composition of illness in preparation.
6. at least one compound as claimed in claim 1 or 2 or physiology as claimed in claim 3, acceptable salt is suitable for treatment or prevents the purposes in the pharmaceutical composition of one or more metabolic disturbance in preparation.
7. purposes as claimed in claim 6, is characterized in that this metabolic disturbance is selected from hyperlipemia, atherosclerosis and relative disease, obesity, hypertension, chronic heart failure, oedema and the hyperuricemia of 1 type and diabetes B, diabetic complication, metabolic acidosis or ketoacidosis, reactive hypoglycemia disease, hyperinsulinemia, impaired glucose metabolism, insulin resistant, metabolism syndrome, different causes.
On at least one compound as claimed in claim 1 or 2 or physiology as claimed in claim 3 acceptable salt in the purposes for the preparation of suppressing in the pharmaceutical composition of sodium dependent glucose cotransporter SGLT2.
9. at least one compound as claimed in claim 1 or 2 or physiology as claimed in claim 3, acceptable salt is being degenerated for the preparation of prevention pancreatic beta cell and/or for improving and/or recover the purposes of the pharmaceutical composition of Pancreatic beta cells function.
On at least one compound as claimed in claim 1 or 2 or physiology as claimed in claim 3 acceptable salt for the preparation of preventing, slow down, postpone or treating due to the purposes having in the pharmaceutical composition of disease that in this patient body needing, liver fat abnormal accumulation causes or illness.
The purposes of acceptable salt in preparing diuretic(s) and/or hypotensive agent on 11. at least one compound as claimed in claim 1 or 2 or physiology as claimed in claim 3.
12. formula II, formula III, formula i.1, formula i.2, formula i.3, formula i.4, formula i.5 or the formula cyanobenzene derivative being replaced by glucopyranose base i.6, comprise its tautomer, steric isomer or its mixture; And acceptable salt on physiology:
Wherein
R
3as defined in claim 1, and
R ' represents H, C
1-4alkyl, (C
1-18alkyl) carbonyl, (C
1-18alkyl) oxygen base carbonyl, aryl carbonyl or aryl-(C
1-3alkyl)-carbonyl, wherein these alkyl or aryls can be by halogen list or polysubstituted;
R
8a, R
8b, R
8c, R
8drepresent independently of one another hydrogen or allyl group, benzyl, (C
1-4alkyl) carbonyl, (C
1-4alkyl) oxygen base carbonyl, aryl carbonyl, aryl-(C
1-3alkyl)-carbonyl and aryl-(C
1-3alkyl)-oxygen base carbonyl or R
ar
br
csi base or ketal or acetal radical, be especially alkylidene group or aryl alkylene ketal or acetal radical, simultaneously two adjacent group R in each situation
8a, R
8b, R
8c, R
8dcan form cyclic ketal or acetal radical or 1,2-, bis-(C
1-3alkoxyl group)-1,2-bis-(C
1-3alkyl)-ethylene bridge, this above-mentioned ethylene bridge forms substituted two with two Sauerstoffatoms and two carbon atoms that are connected of pyranose ring simultaneously
alkane ring, is especially 2,3-dimethyl-2,3-bis-(C
1-3alkoxyl group)-Isosorbide-5-Nitrae-bis-
alkane ring, and alkyl, allyl group, aryl and/or benzyl can be by halogen or C
1-3alkoxyl group list or polysubstituted, and benzyl also can be by two-(C
1-3alkyl) amino replacement; And
R
a, R
b, R
crepresent independently of one another C
1-4alkyl, aryl or aryl-C
1-3alkyl, wherein this aryl or alkyl can be by halogen lists or polysubstituted;
These aryl described in the definition of these above-mentioned groups refer to phenyl or naphthyl simultaneously, are preferably phenyl; And
Alk represents C
1-4alkyl; And
R
1the aldehyde radical that represents chlorine, bromine, cyano group, carboxyl, carboxylicesters, carboxylic acid amides or derivatives thereof, boron or silyl, protected or crested, or the amino of protected or crested, R
1preferably represent Br or CN; And
LG represents leaving group, for example Br, I or-O-(SO
2)-CF
3; And
U represents Cl, Br, I ,-O-CO-C
1-4alkyl ,-O-C (=O)-O-C
1-4alkyl or-OPO (O-C
1-4alkyl)
2.
Applications Claiming Priority (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP06113412.8 | 2006-05-03 | ||
| EP06113412 | 2006-05-03 | ||
| EP06124833.2 | 2006-11-27 | ||
| EP06124833 | 2006-11-27 | ||
| EPPCT/EP2007/051411 | 2007-02-14 | ||
| PCT/EP2007/051411 WO2007093610A1 (en) | 2006-02-15 | 2007-02-14 | Glucopyranosyl-substituted benzonitrile derivatives, pharmaceutical compositions containing such compounds, their use and process for their manufacture |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2007800159285A Division CN101437807A (en) | 2006-05-03 | 2007-05-02 | Glucopyranosyl-substituted benzonitrile derivatives, pharmaceutical compositions containing such compounds, their use and process for their manufacture |
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|---|---|
| CN103601709A true CN103601709A (en) | 2014-02-26 |
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ID=38885607
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| CN201110219008.3A Active CN102351918B (en) | 2006-05-03 | 2007-05-02 | Glucopyranosyl-substituted benzonitrile derivatives, pharmaceutical compositions containing such compounds |
| CN201310616828.5A Pending CN103601709A (en) | 2006-05-03 | 2007-05-02 | Glucopyranosyl-substituted benzonitrile derivatives, pharmaceutical compositions containing such compounds, their use and process for their manufacture |
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| CN201110219008.3A Active CN102351918B (en) | 2006-05-03 | 2007-05-02 | Glucopyranosyl-substituted benzonitrile derivatives, pharmaceutical compositions containing such compounds |
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|---|---|
| US (2) | US7776830B2 (en) |
| EP (1) | EP2024352B1 (en) |
| JP (1) | JP5093524B2 (en) |
| KR (1) | KR101458372B1 (en) |
| CN (2) | CN102351918B (en) |
| AR (1) | AR060831A1 (en) |
| AU (1) | AU2007247218B2 (en) |
| BR (1) | BRPI0711121B8 (en) |
| CA (1) | CA2645638C (en) |
| CY (1) | CY1114187T1 (en) |
| DK (1) | DK2024352T3 (en) |
| EA (1) | EA200802185A1 (en) |
| EC (1) | ECSP088774A (en) |
| ES (1) | ES2422863T3 (en) |
| FI (1) | FIC20240011I1 (en) |
| HR (1) | HRP20130656T1 (en) |
| IL (1) | IL195028A0 (en) |
| MX (1) | MX2008013680A (en) |
| MY (1) | MY146368A (en) |
| NO (1) | NO20083947L (en) |
| NZ (1) | NZ573216A (en) |
| PE (1) | PE20080697A1 (en) |
| PL (1) | PL2024352T3 (en) |
| PT (1) | PT2024352E (en) |
| SI (1) | SI2024352T1 (en) |
| TW (2) | TW201427964A (en) |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106188022A (en) * | 2015-04-30 | 2016-12-07 | 上海医药工业研究院 | The preparation method that Yi Gelie is clean |
| CN111511725A (en) * | 2017-12-19 | 2020-08-07 | 勃林格殷格翰维特梅迪卡有限公司 | Synthesis of 1:1:1 cocrystals of 1-cyano-2- (4-cyclopropyl-benzyl) -4- (β -D-glucopyranos-1-yl) -benzene, L-proline and water |
| CN111511725B (en) * | 2017-12-19 | 2024-04-09 | 勃林格殷格翰维特梅迪卡有限公司 | 1-cyano-2- (4-cyclopropyl-benzyl) -4-) (beta-D-glucopyranos-1-yl) -benzene Synthesis of 1:1:1 Co-crystals of L-proline and Water |
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